Heterocyclic Compounds with Affinity to Muscarinic Receptors

ABSTRACT

The present invention relates to heterocyclic compounds of the formula (I) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, a solvate or hydrate thereof wherein
         the heterocycle comprises two double bonds which may be present at several positions, and which are represented by the dashed lines (---);   the heterocycle contains two heteroatoms,
           W is N or NH;   Y is CH, O or NH, wherein   if Y is O, X 1  is CH and X 2  is C-Z-R2 or C—R3, wherein Z is NH, O, or S; and   if Y is CH or NH, one of X 1  and X 2  is CH or N, wherein if X 1  is CH or N, X 2  is C-Z-R2 or C—R3, and if X 2  is CH or N, X 1  is C-Z-R2 or C—R3, wherein Z is NH or S;   
           R1 is chosen from structures (a), (b) and (c):       

     
       
         
         
             
             
         
       
         
         
           
             R2 is chosen from (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, oxo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkenyloxy, (C 1 -C 6 )alkenylthio, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle (optionally substituted with halogen), phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen; and 
             R3 is chosen from (C 4 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkenyloxy, (C 1 -C 6 )alkenylthio, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen; 
             and optionally, when R2 is an unbranched (C 2 -C 8 )alkyl, R2 links to formula (Ia) 
           
         
       
    
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, a solvate or hydrate thereof,
 
through the X 1 a or X 2 a of formula (Ia), wherein if X 1  is CH or N, X 1 a is CH or N and X 2 a is C-Za-, or
 
if X 1  is C-Z-R2, X 1 a is C-Za- and X 2 a is CH or N, wherein X 1 a or X 2 a having Za links to R2; and
 
the symbols Wa, Ya and Za and the substituent R1 a  have the same meanings as defined previously for the symbols W, Y and Z and the substituent R1, and are not independently selected, each of the symbols Wa, Ya and Za and the substituent R1 a  representing identical symbols and substituents, respectively, as the symbols W, Y and Z and the substituent R1 in the other part of the structure of formula (I). The compounds of the invention have affinity to muscarinic receptors and may be used in the treatment, alleviation or prevention of muscarinic receptor mediated diseases and conditions.

This application claims the benefit of priority of U.S. ProvisionalApplication No. 60/913,584, filed on Apr. 24, 2007, the disclosure ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to new heterocyclic compounds having affinity tomuscarinic receptors, a pharmaceutical composition containing saidcompounds, as well as the use of said compounds for the preparation of amedicament for treating, alleviating or preventing muscarinic receptormediated diseases and conditions.

BACKGROUND OF THE INVENTION

Muscarinic cholinergic receptors mediate the actions of theneurotransmitter acetylcholine in the central and peripheral nervoussystems. Muscarinic receptors comprise five distinct subtypes, denotedas muscarinic M1, M2, M3, M4 and M5 receptors. Each subtype has a uniquedistribution in the central and peripheral nervous systems. The M1receptor is predominantly expressed in the cerebral cortex and isbelieved to be involved in the control of higher cognitive functions;the M2 receptor is the predominant subtype found in heart and isinvolved in the control of heart rate; the M3 receptor is widelyexpressed in many peripheral tissues and is believed to be involved ingastrointestinal and urinary tract stimulation as well as sweating andsalivation; the M4 receptor is present in the brain and may be involvedin locomotion and antipsychotic effects; the M5 receptor is located inthe brain and may be involved in compound addition and in psychoticconditions such as schizophrenia. In view of the key physiological rolesattributed to each of the muscarinic receptor subtypes, extensiveefforts have been made to generate new compounds showing selectiveagonistic or antagonistic properties (see for example EP 0296721; EP0316718; Sauerberg, P. et al., J. Med. Chem., 1992, Vol. 35, No. 22,2274-2283; Ward, J. S. et al., 1992, J. Med. Chem., Vol. 35, No. 22,4011-4019; U.S. Pat. No. 5,527,813; Zlotos, D. P. et al., Exp. Opin.Ther. Patents, Vol. 9, No. 8, 1999, 1029-1053; Plate, R., et al.,Bioorg. Med. Chem. 4 (1996), 227-237; Plate, R. et al., Bioorg. Med.Chem. 8 (2000), 449-454; Del Guidice, M. R. et al., Arch. Pharm. Med.Chem. 2003, 336, 143-154).

A well known example of a M1/M4 preferring muscarinic receptor agonistis the thiadiazole compound xanomeline which in preclinical studies hasa desirable profile, however, in clinical studies displays aunfavourable side effects (see for example the review by Eglen, R. M.,Progress in Medicinal Chemistry, 2005, 43, p. 105-136 and U.S. Pat. No.5,376,668), which seem to be related to M2 receptor mediated activity(e.g. heart rate effects). In addition, xanomeline has a relatively low(in vitro) metabolic stability. Xanomeline related compounds are furtherdisclosed in U.S. Pat. No. 5,527,813. However, representative compoundsdisplay unfavourable side effects which seem to be related to M2 and M3receptor mediated activity (e.g. heart rate effects and salivation,respectively).

Although further research is ongoing to develop therapeutics that havethe selective M1/M4 profile, this has not yet resulted in successfulcandidates. Therefore, there is a need for new selective compounds withthe desired properties.

DESCRIPTION OF THE INVENTION

It has now been found that heterocyclic compounds of the formula (I)

-   -   or a pharmaceutically acceptable salt, a solvate or hydrate        thereof,    -   wherein        -   the heterocycle comprises two double bonds which may be            present at varying positions, and which are represented by            the dashed lines (---);        -   the heterocycle contains two heteroatoms,            -   W is N or NH;            -   Y is CH, O or NH, wherein            -   if Y is O, X₁ is CH and X₂ is C-Z-R2 or C—R3, wherein Z                is NH, O, or S; and            -   if Y is CH or NH, one of X₁ and X₂ is CH or N, wherein                if X₁ is CH or N, X₂ is C-Z-R2 or C—R3, and if X₂ is CH                or N, X₁ is C-Z-R2 or C—R3, wherein Z is NH or S;        -   R1 is chosen from structures (a), (b) and (c):

-   -   -   R2 is chosen from (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl and            (C₂-C₁₀)alkynyl, optionally independently substituted with            one or more substituents chosen from halogen, hydroxy,            cyano, oxo, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,            (C₁-C₆)alkenyloxy, (C₁-C₆)alkenylthio,            (C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₅-C₇)cycloalkyl, a 5-membered            unsaturated heterocycle (optionally substituted with            halogen), phenyl, phenyloxy and phenylthio, wherein the            phenyl group is optionally substituted with halogen; and        -   R3 is chosen from (C₄-C₁₀)alkyl, (C₂-C₁₀)alkenyl and            (C₂-C₁₀)alkynyl, optionally independently substituted with            one or more substituents chosen from halogen, hydroxy,            cyano, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkenyloxy,            (C₁-C₆)alkenylthio, (C₁-C₄)alkoxy(C₁-C₄)alkoxy,            (C₅-C₇)cycloalkyl, a 5-membered unsaturated heterocycle            optionally substituted with halogen, phenyl, phenyloxy and            phenylthio, wherein the phenyl group is optionally            substituted with halogen;        -   and optionally, when R2 is an unbranched (C₂-C₈)alkyl, R2            links to formula (Ia)

-   -   or a pharmaceutically acceptable salt, a solvate or hydrate        thereof,    -   through the X₁a or X₂a of formula (Ia), wherein if X₁ is CH or        N, X₁a is CH or N and X₂a is C-Za-, or    -   if X₁ is C-Z-R2, X₁a is C-Za- and X₂a is CH or N, wherein X₁a or        X₂a having Za links to R2; and    -   the symbols Wa, Ya and Za and the substituent R1a have the same        meanings as defined previously for the symbols W, Y and Z and        the substituent R1 and are not independently selected, each of        the symbols Wa, Ya and Za and the substituent R1a representing        identical symbols and substituents, respectively, as the symbols        W, Y and Z and the substituent R1 in the other part of the        structure of formula (I).

These heterocyclic compounds display affinity to muscarinic receptors,in particular to M1 and/or M4 receptors, having muscarinic receptormodulating, in particular (partially) agonistic, properties.

In addition, compounds of this invention display a higher (in vitro)metabolic stability than the prior art compound xanomeline.

The compounds of the invention are useful for treating, alleviating andpreventing muscarinic receptor mediated diseases and conditions.Preferred compounds are M1 and M4 receptor agonists and may be used inthe treatment of muscarinic M1/M4 mediated diseases and conditions,e.g.—but not limited to—Alzheimer's disease, cognitive impairment,Sjögren's disease, Schizophrenia and antinociception. In particular, thecompounds of the present invention may be used to treat, alleviate orprevent cognitive impairment and psychotic disorders.

In an embodiment of the invention, the compounds have formula (I)wherein R2 is selected from (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl and(C₂-C₁₀)alkynyl, optionally independently substituted with one or moresubstituents selected from halogen, hydroxy, cyano, oxo, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, (C₁-C₆)alkenyloxy, (C₁-C₆)alkenylthio,(C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₅-C₇)cycloalkyl, a 5-membered unsaturatedheterocycle (optionally substituted with halogen), phenyl, phenyloxy andphenylthio, wherein the phenyl group is optionally substituted withhalogen. Preferably, R2 is selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, optionally independently substituted with one ormore substituents selected from halogen, hydroxy, cyano, oxo,(C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₅-C₇)cycloalkyl,tetrahydrofuranyl and phenyl, wherein the phenyl group is optionallysubstituted with halogen. In particular preferred are compounds offormula (I) wherein R2 is selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,optionally substituted with one or more halogen or (C₁-C₆)alkoxy.

Further, in an embodiment of the invention, R3 is selected from(C₄-C₁₀)alkyl, (C₂-C₁₀)alkenyl and (C₂-C₁₀)alkynyl, optionallysubstituted with a substituent selected from (C₅-C₇)cycloalkyl orphenyl, wherein the phenyl group is optionally substituted with halogen.

In a further embodiment of the invention, R1 has the structure (a) or(b), in particular (a).

In another embodiment, the compounds have formula (I) wherein W is N andY is NH, in particular when X₁ is CH and X₂ is the residue C-Z-R2 orC—R3, and Z is O or S and preferably X₂ is the residue C-Z-R2. Zpreferably is S.

In a further embodiment Y is O and Z is O or S, and preferably Z is S.

The term halogen refers to fluoro, chloro, bromo, or iodo. Preferred isfluoro.

The term (C₁-C₁₀)alkyl means a branched or unbranched alkyl group having1-10 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl,n-pentyl, sec-pentyl, hexyl, octyl. In particular in the residue C-Z-R2when Z is O or S, unsubstituted n-pentyl is a preferred alkyl group.Preferred substituted R2 alkyl groups are ethoxyethyl, when Z is O or S,and —(CH₂)₃CF₃ when Z is S.

The term (C₁-C₆)alkoxy means an alkoxy group having 1-6 carbon atoms,wherein the alkyl moiety is as defined above. The term (C₁-C₆)alkylthiohas a similar meaning. The term (C₁-C₄)alkoxy(C₁-C₄)alkoxy means a(C₁-C₄)alkoxy group, the alkyl moiety of which is in turn substitutedwith (C₁-C₄)alkoxy.

The term (C₂-C₈)alkenyl means a branched or unbranched alkenyl grouphaving 2-8 carbon atoms wherein the double bond(s) may be present atdifferent parts of the group, for example vinyl, allyl, butenyl,n-pentenyl, sec-pentenyl, hexenyl, octenyl, etc. In the residue C-Z-R2,when Z is O or S, a preferred alkenyl group is 4-pentenyl and apreferred substituted alkenyl group is 4,4-difluoro-but-3-enyl.

The term (C₁-C₆)alkenyloxy means an alkenyloxy group having 1-6 carbonatoms, wherein the alkenyl moiety is as defined above. The term(C₁-C₆)alkenylthio has a similar meaning.

The term (C₂-C₈)alkynyl means a branched or unbranched alkynyl grouphaving 2-8 carbon atoms wherein the triple bond(s) may be present atdifferent parts of the group, for example ethynyl, propargyl, 1-butynyl,2-butynyl, etc.

The term (C₅-C₇)cycloalkyl means a cyclic alkyl group having 5-7 carbonatoms, thus cyclopentyl, cyclohexyl, cyclopheptyl or cyclooctyl.

The term 5-membered unsaturated heterocycle in the definition of R2means a heterocycle containing 5 atoms, wherein at least one atom is aheteroatom selected from O, N and S, the other atoms being carbon atoms,wherein the heterocycle further at least contains one double bond.Examples are furanyl and pyrrolyl groups.

With reference to substituents, the term “independently” means that thesubstituents may be the same or different from each other.

The compounds of the invention may suitably be prepared by methodsavailable in the art, and as illustrated in the experimental section ofthis description. Some novel and useful intermediates have been foundfor the preparation of the compounds of this invention.

Thus, another embodiment of the invention is a heterocyclic compound ofthe formula (II)

or a pharmaceutically acceptable salt, a solvate or hydrate thereof,wherein

-   -   the heterocycle comprises two double bonds which may be present        at varying positions, represented by the dashed lines (---);    -   the heterocycle comprises two heteroatoms,        -   W* is N, NH or N-2-(trimethylsilyl)ethoxymethyl;        -   Y* is CH, O, N or NR4, wherein R4 is chosen from H,            2-(trimethylsilyl)-ethoxymethyl, —SO₂N(CH₃)₂ and            —SO₂-phenyl; wherein            -   if Y* is O, X₁* is CH and X₂* is tC-Z*-R2* or C—R3*,                wherein Z* is NH, O, or S; and            -   if Y* is CH or NH, one of X₁* and X₂* is CH or N,                wherein if X₁* is CH or N, X₂* is C-Z-R2 or C—R3, and if                X₂* is CH or N, X₁* is C-Z-R2 or C—R3, wherein Z* is NH                or S;    -   R2* is chosen from (C₁-C₈)alkyl, (C₂-C₈)alkenyl and        (C₂-C₈)alkynyl, optionally independently substituted with one or        more substituents chosen from halogen, hydroxy, cyano, oxo,        (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkenyloxy,        (C₁-C₆)alkenylthio, (C₁-C₄)alkoxy(C₁-C₄)alkoxy,        (C₅-C₇)cycloalkyl, a 5-membered unsaturated heterocycle        (optionally substituted with halogen), phenyl, phenyloxy, and        phenylthio, wherein the phenyl group is optionally substituted        with halogen; and    -   R3* is chosen from (C₄-C₁₀)alkyl, (C₂-C₁₀)alkenyl and        (C₂-C₁₀)alkynyl, optionally independently substituted with one        or more substituents chosen from halogen, hydroxy, cyano,        (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkenyloxy,        (C₁-C₆)alkenylthio, (C₁-C₄)alkoxy(C₁-C₄)alkoxy,        (C₅-C₇)cycloalkyl, a 5-membered unsaturated heterocycle        optionally substituted with halogen, phenyl, phenyloxy and        phenylthio, wherein the phenyl group is optionally substituted        with halogen;    -   and optionally, when R2* is an unbranched (C₂-C₈)alkyl, R2*        links to formula (IIa)

or a pharmaceutically acceptable salt, a solvate or hydrate thereof,through X₁*a or X₂*a of formula (IIa), wherein if X₁* is CH or N, X1*ais CH or N and X2*a is C-Z*a-, orif X₁* is C-Z*-R2*, X₁*a is C-Z*a- and X₂*a is CH or N, wherein X₁*a orX₂*a having Z*a links to R2*; andthe symbols W*a, Y*a and Z*a have the same meanings as definedpreviously for the symbols W*, Y* and Z* and are not independentlyselected, each of the symbols W*a, Y*a and Z*a representing identicalsymbols, respectively, as the symbols W*, Y* and Z* in the other part ofthe structure of formula (II).These heterocyclic compounds are useful in the preparation of compoundsof formula (I) wherein R1 has the structure (a). The preferredsubstitution pattern in the compound of formula (II) corresponds to thepreferred substitution pattern of compounds of formula (I).

Also an embodiment of this invention is a heterocyclic compound of theformula (III)

wherein R5 is H and R6 is Br,

or R5 is —Si(CH₃)₃ and R6 is Br or —Si(CH₃)₃,

which compound is useful in the preparation of compounds of formula (I)wherein R1 has the structure (a).

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. The independentsyntheses of these diastereomers or their chromatographic separationsmay be achieved as known in the art by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by the x-ray crystallography of crystalline products orcrystalline intermediates which are derivatized, if necessary, with areagent containing an asymmetric center of known absolute configuration.If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography.

Compounds may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, compounds may formsolvates with water (i.e., hydrates) or common organic solvents, andsuch solvates are also intended to be encompassed within the scope ofthis invention.

Isotopically-labeled compound of formula (I) or pharmaceuticallyacceptable salts thereof, including compounds of formula (I)isotopically-labeled to be detectable by PET or SPECT, also fall withinthe scope of the invention. The same applies to compounds of formula (I)labeled with [¹³C]-, [¹⁴C]-, [³H]-, [¹⁸F]-, [¹²⁵I]- or otherisotopically enriched atoms, suitable for receptor binding or metabolismstudies.

The term “pharmaceutically acceptable salt” refers to those salts thatare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. They can be prepared in situwhen finally isolating and purifying the compounds of the invention, orseparately by reacting them with pharmaceutically acceptable non-toxicbases or acids, including inorganic or organic bases and inorganic ororganic acids.

The compounds of the invention may be administered enterally orparenterally. The exact dose and regimen of these compounds andcompositions thereof will be dependent on the biological activity of thecompound per se, the age, weight and sex of the patient, the needs ofthe individual subject to whom the medicament is administered, thedegree of affliction or need and the judgment of the medicalpractitioner. In general, parenteral administration requires lowerdosages than other methods of administration which are more dependentupon adsorption. However, the dosages for humans are preferably 0.001-10mg per kg body weight, more preferably 0.01-1 mg per kg body weight. Ingeneral, enteral and parenteral dosages will be in the range of 0.1 to1,000 mg per day of total active ingredients.

The medicament manufactured with the compounds of this invention mayalso be used as adjuvant in therapy. In such a case, the medicament oris administered in a combination treatment with other compounds usefulin treating such disease states. Also pharmaceutical combinationpreparations comprising at least one compound of the present inventionand at least one other pharmacologically active substance are consideredin this respect.

Mixed with pharmaceutically suitable auxiliaries, e.g. as described inthe standard reference “Remington, The Science and Practice of Pharmacy”(21^(st) edition, Lippincott Williams & Wilkins, 2005, see especiallyPart 5: Pharmaceutical Manufacturing) the compounds may be compressedinto solid dosage units, such as pills or tablets, or be processed intocapsules or suppositories. By means of pharmaceutically suitable liquidsthe compounds can also be applied in the form of a solution, suspensionor emulsion.

For making dosage units, e.g. tablets, the use of conventional additivessuch as fillers, colorants, polymeric binders and the like, iscontemplated. In general, any pharmaceutically suitable additive whichdoes not interfere with the function of the active compounds can beused.

Suitable carriers with which the compounds of the invention can beadministered include for instance lactose, starch, cellulose derivativesand the like, or mixtures thereof, used in suitable amounts.Compositions for intravenous administration may for example be solutionsof the compounds of the invention in sterile isotonic aqueous buffer.Where necessary, the intravenous compositions may include for instancesolubilizing agents, stabilizing agents and/or a local anesthetic toease the pain at the site of the injection.

Pharmaceutical compositions of the invention may be formulated for anyroute of administration and comprise at least one compound of thepresent invention and pharmaceutically acceptable salts thereof, withany pharmaceutically suitable ingredient, excipient, carrier, adjuvantor vehicle.

By “pharmaceutically suitable” it is meant that the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In an embodiment of the invention, a pharmaceutical pack or kit isprovided comprising one or more containers filled with one or morepharmaceutical compositions of the invention. Associated with suchcontainer(s) can be various written materials such as instructions foruse, or a notice in the form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals products,which notice reflects approval by the agency of manufacture, use, orsale for human or veterinary administration.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described in this document. All publications, patentapplications, patents, and other references mentioned herein areincorporated by reference in their entirety. In case of conflict, thepresent specification, including definitions, will control.

The following examples are only intended to further illustrate theinvention in more detail, and therefore these examples are not deemed torestrict or limit the scope of the invention in any way.

EXAMPLES §1. Materials and Methods

Nuclear magnetic resonance spectra (¹H NMR and ¹³C NMR, APT) weredetermined in the indicated solvent using a Bruker ARX 400 (1H: 400 MHz,¹³C: 100 MHz) at 300 K, unless indicated otherwise. ¹⁹F NMR and ¹³C NMRexperiments were carried out on a Varian Inova 500 spectrometeroperating at 11.74 T (499.9 MHz for ¹H, 125.7 MHz for ¹³C; 50.7 Mhz,470.4 MHz for ¹⁹F) using a 5 mm SW probe. The spectra were determined indeuterated chloroform or dichloromethane obtained from Cambridge IsotopeLaboratories Ltd. Chemical shifts (δ) are given in ppm downfield fromtetramethylsilane (1H, 13C) or CCl3F (¹⁹F). Coupling constants J aregiven in Hz. Peakshapes in the NMR spectra are indicated with thesymbols ‘q’ (quartet), ‘dq’ (double quartet), ‘t’ (triplet), ‘dt’(double triplet), ‘d’ (doublet), ‘dd’ (double doublet), ‘s’ (singlet),‘bs’ (broad singlet) and ‘m’ (multiplet). NH and OH signals wereidentified after mixing the sample with a drop of D₂O.

Flash chromatography refers to purification using the indicated eluentand silica gel (either Acros: 0.030-0.075 mm or Merck silica gel 60:0.040-0.063 mm).

Column chromatography was performed using silica gel 60 (0.063-0.200 mm,Merck).

Melting points were recorded on a Büchi B-545 melting point apparatus.

Mass spectra (MS) were recorded on a Micromass QTOF-2 instrument withMassLynx application software for acquisition and reconstruction of thedata. Exact mass measurement was done of the quasimolecular ion [M+H]⁺.Accurate mass measurements were performed using a JEOL JMS-SX/SX 102 ATandem Mass Spectrometer using Fast Atom Bombardement (FAB). A resolvingpower of 10,000 (10% valley definition) for high resolution FAB massspectrometry was used.

All reactions involving moisture sensitive compounds or conditions werecarried out under an anhydrous nitrogen atmosphere.

Reactions were monitored by using thin-layer chromatography (TLC) onsilica coated plastic sheets (Merck precoated silica gel 60 F254) withthe indicated eluent. Spots were visualised by UV light (254 nm) or 12.

Extinction coefficients were determined with a HP 8453 UV-Visspectrophotometer.

Analytical high performance liquid chromatography (HPLC) was performedon a C18 column (Inertsil ODS-3, particle size 3 mm; 4.6 mm 50 mm) usingthe following elution gradient: linear gradient of 5% to 95% aqueousCH₃CN containing 0.04% HCO₂H over 5 min, then 95% aqueous CH₃CNcontaining 0.04% HCO₂H for 2 min at 2.0 ml min⁻¹. Products were detectedat λ=254 nm.

Liquid Chromatography-Mass Spectrometry (LC-MS), Method A

The LC-MS system consists of 2 Perkin elmer series 200 micro pumps. Thepumps are connected to each other by a 50 μl tee mixer, connected to aGilson 215 auto sampler. The method is as follows:

step total time flow (ul/min) A (%) B (%) 0 0 2000 95 5 1 1.8 2000 0 1002 2.5 2000 0 100 3 2.7 2000 95 5 4 3.0 2000 95 5 A = 100% Water with0.025% HCOOH and 10 mmol NH4HCOO pH = +/−3 B = 100% ACN with 0.025%HCOOH

The auto sampler has a 2 μl injection loop. The auto sampler isconnected to a Waters Atlantis C18 30*4.6 mm column with 3 μm particles.The column is thermo stated in a Perkin Elmer series 200 column oven at40° C. The column is connected to a Perkin Elmer series 200 UV meterwith a 2.7 μl flowcel. The wavelength is set to 254 nm. The UV meter isconnected to a Sciex API 150EX mass spectrometer.

The mass spectrometer has the following parameters: Scanrange: 150-900a.m.u.; polarity: positive; scan mode: profile; resolution Q1: UNIT;step size: 0.10 a.m.u.; time per scan: 0.500 sec; NEB: 10; CUR: 10 IS:5200; TEM: 325; DF: 30; FP: 225 and EP: 10.

The light scattering detector is connected to the Sciex API 150. Thelight scattering detector is a Sedere Sedex 55 operating at 50° C. and 3bar N₂.

The complete system is controlled by a G3 powermac.

Liquid Chromatography-Mass Spectrometry (LC-MS), Method B

The LC-MS system consists of an Agilent series 1100 system consisting ofthe following components:

G1379A Degasser

G1312A Binary Pump

The pumps are connected to a G1313A ALS auto sampler.The method is as follows:

total flow Step Time (min) (ml/min) A (%) B (%) 0 0 1.0 2 98 1 10.5 1.098 2 2 18.0 1.0 98 2 3 18.1 1.0 2 98 4 24.0 1.0 2 98 A: Acetonitrilewith 0.1% HCOOH or Acetonitrile with 10 mM NH3 B: Water with 0.1% HCOOHor Water with 10 mM NH3

The auto sampler is connected to a Zorbax Extend C18 column 150×4.6 mmwith 3.5 um particles.

The column is thermo stated in a G1316A Colcomm column oven at 35° C.

The column is connected to a G1315B DAD diode array detector. Thewavelength range is set from 220 to 320 nm. The UV meter is connected toG1946D MSD mass spectrometer, operating in electron spray mode.

The mass spectrometer has the following parameters:

Scan range: 100-800 amu Polarity: Positive & Negative Mode: Scan Stepsize: 0.20 Cycle time: 1.04 sec % Cycle time: 50% Drying gas: NitrogenGas flow: 10 l/min Gas temp.: 300° C. Neb. Press.: 30 psi CapillaryVolt.: 3000 V

An Alltech ELSD 2000 detector is connected parallel with the MSD. Theflow is split after the DAD.

The ELSD has the following parameters:

Drying gas: Nitrogen Gas flow: 1.5 l/min Drift tube temp.: 39° C.Impactor: On

§2. Abbreviations

n-BuLi n-butyl lithiumt-BuOH t-butanoldba dibenzylideneacetoneDCM dichloromethaneDMF N,N′-dimethylformamideDMF-DMA N,N′-dimethylformamide dimethyl acetalDMSO dimethylsulfoxideEtOH ethanolEt2O diethyl etherg gram(s)h hour(s)Me methylMeI methyl iodideMeOH methanolmg milligram(s)min minute(s)ml milliliter(s)m.p. melting point c.q. melting range

NBS N-bromosuccinimide NIS N-iodosuccinimide

PE petroleum ether (40-65° C.)Rt retention time (LC/MS)

SEM-Cl (2-Chloromethoxy-ethyl)-trimethylsilane

TBAF tetrabutylammonium fluorideTHF tetrahydrofuran

§3. General Aspects of Syntheses

Different synthetic routes for the preparations of compounds of thepresent invention illustrated in formula I are described and easilyprepared from readily available starting materials. More generalinformation on pyrazole, imidazole and isoxazole chemistry, see forexample: J. A. Joule, K. Mills and G. F. Smith, “HeterocyclicChemistry”, third edition, Stanley Thornes (Publishers) Ltd.,Cheltenham, 1998. More information on addition and subsequent removal ofprotective groups in organic synthesis can be found in: T. W. Greene andP. G. M. Wuts, “Protective Groups in Organic Synthesis”, third edition,John Wiley & Sons, Inc., New York, 1999.

The selection of the particular method depends on factors such as thecompatibility of functional groups with the reagent used, thepossibility to use protecting groups, catalysts, activating and couplingreagents and the ultimate structural features present in the finalcompound being prepared.

In an example of the general procedure (scheme 1), nicotinoyl chloridehydrochloride (1) is converted to the N-methyl-N-methoxyamide (2) in thepresence of a base and reacted with hexyl-lithium (J. Med. Chem., 35,1992, 2392-2406) to produce 1-pyridin-3-yl-heptan-1-one (3).

Mild α-methylenation of compound 3 (J. Org. Chem., 71, 2006, 2538-2541)afforded 2-methylene-1-pyridin-3-yl-heptan-1-one (4), which was reactedwith hydrazine (Synthesis, 1989, 320-321) to produce1-(4-pentyl-3-pyridin-3-yl-4,5-dihydropyrazol-1-yl)-ethanone (5).Oxidation of a 2-pyrazoline to a pyrazol can be accomplished usingmethods well known to those skilled in the art. Specific conditions are:activated MnO₂ in dichloroethane (EP0094555) to produce compound 6,which was deprotected under basic conditions to afford compound 7. The3-(4-pentyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridinederivate (9) was obtained from compound 8 by quarternizing the pyridinemoiety with CH₃I and reducing the corresponding pyridinium salt withNaBH₄ (Arch. Pharm. Pharm. Med. Chem., 336, 2003, 143-154).

In another example of the general procedure (scheme 2), readilyavailable pyridin-3-yl-acetic acid (10) is converted to theN-methyl-N-methoxyamide derivate (12), which is reacted with BuLi toproduce 1-pyridin-3-yl-hexan-2-one (13). N,N-dimethylformamidedimethylacetal treatment of 13 furnished the enamine (14) which isconverted to the pyrazol (15). The synthesis of3-(4-Butyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (16) isillustrated in scheme 2 according to the two step sequence shown inscheme 1.

In yet another example of the general procedure (scheme 3),3-(4-bromo-1H-pyrazol-3-yl)-pyridine (20A) or its iodo analog (20B)(Bioorganic & Medicinal Chemistry, 4, 1996, 227-237) is used asprecursor for the synthesis of compounds of the general formula I. Thedi-lithio derivate (Bioorganic & Medicinal Chemistry, 8, 2000,2317-2335) of 20A, prepared on multigram scale by pyrazol-NHdeprotonation and bromine-lithium exchange (2.1 equiv. n-Buli, THF, −78°C., 2 hr), was trapped with a disulfide (for examplemethyldisulfanylmethane) affording3-(4-methylsulfanyl-1H-pyrazol-3-yl)-pyridine 21A, which was convertedto the 1,2,5,6-tetrahydro-1-methylpyridine derivate 22A according to thetwo step sequence shown in scheme 1.

The generation of anions at the ortho position of the aromatic systemsemployed in the synthetic procedures described in this application isperformed according to a general synthetic strategy known as DirectedOrtho Metalation (DOM). Within this area, a number of functional groupsknown as Directed Metalation Groups (DMG's) have been studied for thispurpose.

The dimethylsulfonamide group as Directing Metalation Group (DMG) in theN₁-position of 3-pyridin-3-yl-pyrazole-1-sulfonic acid dimethylamide(23) enables the lithiation of the 5-position and thereby itsfunctionalisation (Chem. Ber., 124, 1991, 1639-1650). The5-lithioderivate of 23, prepared on multigram scale by α-metallation(1.0 equiv, t-Buli, THF, −78° C., 1 hr), was trapped (J. Org. Chem., 64,1999, 5366-5370) with a disulfide (for example 1-butyldisulfanylbutane)to afford 5-butylsulfanyl-3-pyridin-3-yl-pyrazol-1-sulfonic aciddimethylamide 24, which was deprotected (25) and converted to the1,2,5,6-tetrahydro-1-methylpyridine derivate 26 according to the twostep sequence shown in scheme 1.

Another synthetic route for the preparations of compounds of the presentinvention illustrated in formula I is described in scheme 4. Theintroduction of the 2-(trimethylsilyl)-ethoxymethyl group (SEM) as aprotective group (Tetrahedron Letters, 39, 1998, 5171-5174) afforded amixture of compounds 27A and 27B. Subsequent bromine-lithium exchange(1.1 equiv. n-Buli, THF, −78° C., 1 hr) and reacting this4-lithioderivate of 27A/B with S₈ generates the intermediate lithiumaryl thiolate (J. Org. Chem., 69, 2004, 3236-3239) of3-pyridin-3-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-thiol.This intermediate was trapped with 4-bromo-1,1,1-trifluoro-butane toafford a mixture of 28A and 28B. Subsequent removal of the SEMprotecting group resulted in the desired3-[4-(4,4,4-trifluoro-butylsulfanyl)-1H-pyrazol-3-yl]-pyridine 21B,which was converted to the 1,2,5,6-tetrahydro-1-methylpyridine derivate22B according to the two step sequence shown in scheme 1.

In another aspect, 3-(4-iodo-1H-pyrazol-3-yl)-pyridine (20B, scheme 5)is employed as starting material for compounds of the present inventionillustrated in formula I.

The 4-lithioderivate of the SEM protected derivative 29A/B, preparedaccording to the corresponding compounds 27A/B (scheme 4), was reactedwith trimethyl borate followed by in situ hydrogen peroxide oxidation(J. Heterocyclic Chem., 31, 1994, 1377-1380) to afford the corresponding3-pyridin-3-yl-1-(2-trimethylsilanyl-1-ethoxymethyl)-1H-pyrazol-4-ol(30, one isomer given). Alkylation of the 4-hydroxy derivate 30 can beaccomplished using methods well known in the art, for example, byreacting compound 30 with K₂CO₃ in DMF in the presence of a variety of(aryl)alkyl halides, for example (3-bromo-propyl)-benzene, to generatecompound 31A (one isomer given). Subsequent removal of the SEM groupresulted in 3-[4-(3-phenyl-propoxy)-1H-pyrazol-3-yl]-pyridine (32A),which was converted to the 1,2,5,6-tetrahydro-1-methylpyridine derivate33A according to the two step sequence shown in scheme 1.

Scheme 6 illustrates two alternative methods of preparing3-(4-alkoxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridinecompounds.

The mixture of readily available SEM protected pyrazoles 29A/B wasconverted to a mixture of 34A/B by the efficient two step sequencedescribed in scheme (quarternizing the pyridine moiety with CH₃I andreducing the corresponding pyridinium salt with NaBH₄).

Techniques for the formation of C—O bonds have been reported (e.g. J.Am. Chem. Soc., 123, 2001, 10770). More precisely, an efficienttransformation of primary alcohols with the 4-iodo-pyrazole analog(34A/B) could be achieved using the Cul/1,10-phenanthroline catalyzedcross-coupling methodology (Organic Letters, 4, 2002, 973-976).Subsequent deprotection of compound 35A (one isomer given) yielded3-(4-hexyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(33B).

In an alternative synthetic sequence (scheme 6), C—O bond formation canbe accomplished using the aforementioned Cul/1,10-phenanthrolinecatalyzed cross-coupling methodology to generate compound 31G. Thesynthesis of compound 33G has been illustrated in scheme 6, according tothe procedures illustrated in scheme 5.

One aspect of the invention relates to bis3-(4-alkylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridinederivatives (for example compound 22C, scheme 7) that bind to and canactivate muscarinic receptors (J. Med. Chem., 44, 2001, 4563-4576).

Introdution of the phenylsulfonyl as protective group (starting from20A) was accomplished regio-selectively to generate3-(1-phenylsulfonyl-4-bromo-1H-pyrazol-3-yl)-pyridine (36A from 20A).

The cross-coupling of aliphatic and aromatic thiols and aryl bromidescan be mediated by a Pd₂(dba)₃/Xantphos catalytic system in refluxingxylene to afford the corresponding aryl thioethers (Organic Letters, 6,2004, 4587-4590, Tetrahedron, 61, 2005, 5253-5259).

Using this methodology, 36A was converted to the protectedbis-alkylsulfanyl-pyrazol derivative 37. Removal of theNi-phenylsulfonyl group can be accomplished using methods well known tothose skilled in the art, for example, optionally reacting compound 37with potassium hydroxide in diethylene glycol in the presence ofhydrazine. Quarternizing the (bis)-pyridine moiety with CH₃I andreducing the corresponding (bis)-pyridinium salt with NaBH₄ affordedpyrazol derivative 22C.

Scheme 7 illustrates an alternative method for preparing3-(4-alkylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridinederivatives, so can be used to synthezise compounds presented in scheme3 & 4 (22A and 22B respectively), the main feature being theavailability of the parent thiol.

Another illustration of the preparation of compounds of the presentinvention of formula I is shown in scheme 8.

Straightforward nitration (Chem. Ber., 88, 1955, 1577) of pyrazolederivative 19, afforded 3-(4-nitro-1H-pyrazol-3-yl)-pyridine (38), whichwas reduced to the corresponding 3-pyridin-3-yl-1H-pyrazol-4-ylamine(39) and reacted with an acid chloride, for example butyryl chloride, togenerate the amide (40). Subsequent conversion to the1,2,5,6-tetrahydro-1-methylpyridine derivate 41 was done accordingly tothe two step sequence shown in scheme 1. Subsequent LiAlH₄ reduction ofthe amide generatesbutyl-[3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-yl]-amine(42).

Scheme 9 illustrates the preparation of 3-(4-alkynyl(andalkenyl)-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridinederivatives as compounds of the formula I.

3-(1-Phenylsulfonyl-4-bromo-1H-pyrazol-3-yl)-pyridine (36A, scheme 7) orits iodo analog 36B (scheme 9) are excellent substrates for Sonogashiracouplings with terminal acetylenes (Tetrahedron Letters, 38, 1997,7835-7838., Eur J. Org. Chem., 2006, 3283-3307). Catalysis withPdCl₂(PPH₃)₂ in the presence of CuI (excess Et₃N, DMF, 80° C., 2 hr) and(for example) hex-1-yne generates compound 43A. Subsequent deprotection(accordingly to scheme 7), followed by the two step sequence shown inscheme 1, afforded3-(4-hex-1-ynyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(45A).

The scope and reactivity of compound 36A (or 36B) is further illustratedby the Suzuki-Miyaura coupling reactions with (for example)alkenylboronic acids. Catalysis with Pd(OAc)₂ and the effective S-Phosin the presence of K₃PO₄ and (for example) (E)-hexen-1-ylboronic acid(J. Am. Chem. Soc., 127, 2005, 4685-4696) afforded the alkenyl 46A.Subsequent deprotection, followed by the two step sequence shown inscheme 1 afforded3-(4-hex-1-enyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(47A).

In another aspect, 3-(4-iodo-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane(48, Bioorganic & Medicinal Chemistry 8, 2000, 449-454) is employed asstarting material for compounds of the present invention of formula I(scheme 10).

Referring to scheme 3, the di-lithio derivative (Bioorganic & MedicinalChemistry, 8, 2000, 2317-2335) of 48, (2.1 equiv. n-Buli, THF, −78° C.,2 hr), was trapped with a disulfide (for example1-butyldisulfanyl-butane) to afford the corresponding3-(4-butylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane 49A.

Scheme 10 illustrates an alternative—but also general—method ofpreparing 3-(4-alkylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octanederivatives. So, compound 48 could be converted by thePd₂(dba)₃/Xantphos catalytic system (analogous to scheme 7, but in DMFat 120° C.) yielding the corresponding aryl thioether 49B, in a singlestep without protection.

The mixture of readily available SEM protected pyrazoles 50 (one isomergiven) was converted to a mixture of 51A by the Cul/1,10-phenanthrolinecatalyzed cross-coupling methodology as described in scheme 6, howeverusing different conditions. Subsequent deprotection of 51A yields thecorresponding 3-(4-butoxy-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]-octane52A.

A further illustration of the preparation of compounds of the presentinvention of formula I is shown in scheme 11.

The readily available 1-aza-bicyclo[3.2.1]octan-6-one (53), (J. Med.Chem., 36, 1993, 683-689) was converted to6-(1H-pyrazol-3-yl)-1-azabicyclo[3.2.1]-6-ol (55), analogous to anefficient two step sequence (Bioorganic & Medicinal Chemistry 8, 2000,449-454). Attempts to improve the yield of dehydratation of the alcohol(55) was accomplished by acylation (56) (Heterocycles, 24, 1986,971-977) and subsequent elimination in the heat (185° C.). Reduction ofthe enamine (57) gave the anticipated endo 1-azabicyclo[3.2.1]derivative(58). Iodination (Bioorganic & Medicinal Chemistry, 4, 1996, 227-237)and introduction of pentane-1-thiol by the Pd₂(dba)/Xantphos catalyticsystem (accordingly to scheme 7) affordedendo-6-(4-pentylsulfanyl-1-H-pyrazol-3-yl)-1-azabicyclo[3.2.1]octane(60A).

In scheme 12, yet another illustration of the preparation of compoundsof the present invention of formula I is shown.

Commercially available 3-pyridinealdoxime (61) is converted to itschlorohydroxyimino derivative (US 2004/0157900) which is converted tonicotinonitrile oxide (Tetrahedron, 61, 2005, 4363-4371) “in situ” andreacted with 1,2-bis-trimethylsilanyl-ethyne (Chem. Ber., 107, 1974,3717-3722) to afford the 1,3-dipolar cycloaddition product3-(4,5-bis-trimethylsilanyl-isoxazol-3-yl)-pyridine (62).Halogen-induced ipso desilylation resulted in the4-bromo-5-trimethylsilanyl derivative (63). Subsequent desilylation withNH₄OH (Chem. Ber., 112, 1979, 2829-2836) generates3-(4-bromo-isoxazol-3-yl)-pyridine (64).

The isoxazole-pyridine derivatives 62, 63 and 64 are new compounds and,as such, embodiments of the present invention.

Introduction of (for example) butane-1-thiol to compound 64 by thePd₂(dba)₃/Xantphos catalytic system (accordingly to scheme 7, 10 and 11)afforded 3-(4-butylsulfanyl-isoxazol-3-yl)-pyridine (65A). Quarternizingthe pyridine moiety, preferentially with sulfuric acid dimethyl esterand reducing the corresponding pyridinium salt with NaBH₄, generates thecorresponding3-(4-butylsulfanyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(66A).

Scheme 13 illustrates the preparation of 3-(4-alkynyl(andalkenyl)-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine derivativesas compounds of the formula I.

3-(4-Bromo-isoxazol-3-yl)-pyridine (64) is an excellent substrate forSonogashira couplings with (terminal) acetylenes using an analog of themethodology described in scheme 9.

Subsequent conversion of these alkynyl derivatives (scheme 13, forexample 69A) using the quarternizing and reduction conditions describedin scheme 12, afforded the corresponding3-(4-alkynyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridinederivatives (for example 70A).

The scope and reactivity of compound 64 is further illustrated by theSuzuki-Miyaura coupling reactions with (for example) alkenylboronicacids using the methodology described in scheme 9. Subsequent conversionof these alkenyl derivatives (scheme 13, for example 67A) using thequarternizing and reduction conditions described in scheme 12, affordedthe corresponding3-(4-alkenyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridinederivatives (for example 68A).

The preparation of compounds of the present invention of formula I isfurther shown in scheme 14.

3-Trimethylstannanyl-pyridine (71), (Eur. J. Org. Chem., 2002, 2126),obtained from 3-bromo-pyridine using Knochel methodology (Angew. Chem.,Int. Ed., 39, 2000, 4414-4435) is coupled under Stille conditions(Toluene, 120° C., PdCl₂(PPH₃)₂ with4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (72)(Tetrahedron Letters, 39, 1998, 5171-5174) to afford the3-[5-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine(73). Introduction of (for example) pentane-1-thiol by thePd₂(dba)₃/Xantphos catalytic system (accordingly to scheme 12) affordedthe corresponding 5-pentylsulfanyl-isoxazole derivative (74A).Quarternizing the pyridine moiety (CH₃I) and reducing the correspondingpyridinium salt with NaBH₄ (75A) followed by subsequent removal of theSEM group, generates3-[5-pentylsulfanyl-3H-imidazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine(76A).

Alternative to the conversion of 74A to 76A, deprotection of 74B (scheme14, compound 77) followed by quaternization and reduction generates thedesired3-[5-hexylsulfanyl-3H-imidazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine(76B).

§4. Syntheses of Specific Compounds N-Methoxy-N-methyl-nicotinamide(Compound 2, Scheme 1)

Nicotinoyl chloride hydrochloride (compound 1) (10 g, 56 mmol) and 6.28g of N,O-dimethyl-hydroxylamine.HCl (72.8 mmol) were combined in 200 mldichloromethane. To this mixture was added 18.14 ml of pyridine (in 15minutes at 0° C.). The reaction mixture was subsequently stirred for 4hours at room temperature. The reaction was concentrated in vacuo. Theresulting residue was taken up in dichloromethane and H₂O (0° C.),washed with a 2N NaOH solution followed by brine, dried (Na₂SO₄),filtered and concentrated in vacuo. Purification by flash chromatography(MeOH/triethylamine 97/3) afforded compound 2 as an oil (6.92 g, 74%).¹H-NMR (200 MHz, CDCl₃) δ 8.96 (d, J=2 Hz, 1H), 8.69 (d, J=5 Hz, 2 Hz,1H), 8.04 (dt, J=8 Hz, 2 Hz, 1H), 7.41-7.32 (m, 1H), 3.56 (s, 3H), 3.40(s, 3H). (TLC MeOH/triethylamine R_(f) 0.19).

1-Pyridin-3-yl-heptan-1-one (Compound 3, Scheme 1)

To a solution of anhydrous THF (15 ml) containing compound 2 (1.0 g,6.02 mmol) was added 3.08 ml (7.66 mmol) of hexyl-lithium (2.5 M inhexane) dropwise at −78° C. under N₂. After the addition, the resultingsolution was stirred for 30 minutes at −78° C. The mixture was allowedto warm to ambient temperature and poured into a NH₄Cl solution (10 g/50ml H₂O, 0° C.). Ethyl acetate was added and the organic layer was washedwith a 5% NaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated invacuo. The resulting residue was purified by flash chromatography(diethyl ether/PE 1:1) to give compound 3 as an oil (0.91 g, 78%).¹H-NMR (200 MHz, CDCl₃): δ 9.18 (d, J=2 Hz, 1H), 8.78 (d, J=5 Hz, 2 Hz,1H), 8.24 (dt, J=8 Hz, 2 Hz, 1H), 7.47-7.37 (m, 1H), 2.99 (t, J=7 Hz,2H), 1.84-1.65 (m, 2H), 1.47-1.25 (m, 6H), 0.90 (bt, J=7 Hz, 3H).

2-Methylene-1-pyridin-3-yl-heptan-1-one (Compound 4, Scheme 1)

To 1 g (5.2 mmol) of compound 3, dissolved in 10 ml of MeOH, was added0.1 ml of piperidine, 0.1 ml of acetic acid and 3 ml of an aqueousformaldehyde solution (37% formaldehyde in water). The mixture washeated to reflux for 48 hour. The mixture was cooled and concentrated invacuo. Ethyl acetate was added and the organic layer was washed with a5% NaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated in vacuo.The resulting residue was purified by flash chromatography (diethylether/PE 1/1) to give compound 4 as an oil (1.05 g, 95%). ¹H-NMR (200MHz, CDCl₃): δ 8.94 (d, J=2 Hz, 1H), 8.76 (d, J=5 Hz, 2 Hz, 1H), 8.05(dt, J=8 Hz, 2 Hz, 1H), 7.46-7.35 (m, 1H), 5.94 (s, 1H), 5.64 (s, 1H),2.48 (bt, J=7 Hz, 2H), 1.60-1.25 (m, 6H), 0.99-0.82 (m, 3H).

1-(4-Pentyl-3-pyridin-3-yl-4,5-dihydropyrazol-1-yl)-ethanone (Compound5, Scheme 1)

Compound 4 (3.37 g, 16.6 mmol) and 5.89 ml of hydrazine hydrate weredissolved in 50 ml of acetic acid and heated to reflux for 1.5 hour. Themixture was cooled and concentrated in vacuo. Ethyl acetate was addedand the organic layer was washed with a 5% NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting residue waspurified by flash chromatography (ether/ethyl acetate 1/1) to givecompound 4. (amorphous, 2.92 g, 68%). ¹H-NMR (600 MHz, D₆DMSO): δ 8.92(d, J=2 Hz, 1H), 8.67-8.64 (m, 1H), 8.07 (bd, J=8 Hz, 1H), 7.39-7.36 (m,1H), 4.04 (t, J=10 Hz, 1H), 3.96 (dd, J=10 Hz, J=5 Hz, 1H), 3.67-3.61(m, 1H), 2.40 (s, 3H), 1.76-1.69 (m, 1H), 1.50-1.42 (m, 1H), 1.39-1.22(m, 6H), 0.87 (bt, J=7 Hz, 3H).

3-(4-Pentyl-1H-pyrazol-3-yl)-pyridine (Compound 7, Scheme 1)

Compound 5 (0.9 g, 3.47 mmol) and 3.01 g of MnO₂ (10 eq.) were combinedin dichloroethane (100 ml) and warmed to reflux for 2 hours (Dean Starkconditions).

Additional MnO₂ (6.02 g) was added and the mixture was refluxed foranother 12 hours. The mixture was cooled, filtered and the filtrate waswashed thoroughly with dichloroethane/isopropyl alcohol (1/1). Thismixture was concentrated in vacuo to afford the oxidation product (6)(TLC ethyl acetate R_(f) 0.20), contaminated with some starting material(5) (TLC ethyl acetate R_(f) 0.27) and already deacylated product (7)(TLC ethyl acetate R_(f) 0.12). This mixture (0.64 g) was used as in thenext step without further purification.

The aforementioned material was dissolved in 5 ml of EtOH and 5 ml of 2N NaOH and the reaction mixture was refluxed for 4 hours. The mixturewas cooled and concentrated in vacuo. Ethyl acetate was added and theorganic layer was washed with a 5% NaHCO₃ solution, dried (Na₂SO₄),filtered and concentrated in vacuo. The resulting residue was purifiedby flash chromatography (ethyl acetate) to afford the title compound (7)as an oil (344 mg, 1.6 mmol, 46% (overall)). ¹H-NMR (200 MHz, CDCl₃): δ8.88 (d, J=2 Hz, 1H), 8.60 (dd, J=5 Hz, 2 Hz, 1H), 7.92 (dt, J=8 Hz, 2Hz, 1H), 7.47 (bs, 1H), 7.38-7.33 (m, 1H), 2.62 (t, J=7 Hz, 2H),1.64-1.55 (m, 2H), 1.36-1.28 (m, 6H), 0.85 (bt, J=7 Hz, 3H).

3-(4-Pentyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 9, Scheme 1)

Iodomethane (0.08 ml, 1.28 mmol) was added to a solution of 7 (130 mg,0.6 mmol) in acetone (10 ml). After heating for 12 hours, the reactionmixture was cooled and the precipitated crystals were filtered, washedwith diethyl ether and dried to afford compound 8. To a cooled (−30° C.)suspension of this pyridinium iodide derivative (8) in MeOH (15 ml),sodium borohydride (90 mg, 2.4 mmol) was added in small portions. Themixture was allowed to warm to ambient temperature and poured into asaturated NH₄Cl solution (0° C.). The solvent was (partly) removed underreduced pressure. Ethyl acetate was added and the organic layer waswashed with a concentrated NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting residue was purified by flashchromatography (MeOH/triethylamine 97/3) to afford the title compound 9(amorphous, 63 mg, 45% (overall)). ¹H-NMR (200 MHz, CDCl₃) δ 7.35 (bs,1H), 6.07-6.00 (bs, 1H), 3.33-3.25 (m, 2H), 2.64-2.35 (m, 6H), 2.45 (s,3H), 1.68-1.50 (m, 2H), 1.41-1.28 (m, 4H), 0.90 (bt, J=7 Hz, 3H).

N-Methoxy-N-methyl-2-pyridine-3-yl-acetamide (Compound 12, Scheme 2)

To a solution of anhydrous dichloromethane (200 ml) containing compound10 (15.35 g, 88.4 mmol) was added 14.93 ml (163.3 mmol) of oxalylchloride and a few drops of DMF. The mixture was gently refluxed for 8hours under N₂. The mixture was cooled and concentrated, re-dissolved indichloromethane and concentrated. The residue was dissolved in 200 ml ofanhydrous dichloromethane and 11.09 g (113.7 mmol) ofN,O-Dimethyl-hydroxylamine.HCl was added. To this mixture (0° C.) wasadded 2.73 ml of pyridine (in 15 minutes). The reaction mixture wassubsequently stirred for 4 hours at room temperature. The reaction wasconcentrated in vacuo. The resulting residue was taken up indichloromethane and H₂O (0° C.), washed with a 2N NaOH solution followedby brine, dried (Na₂SO₄), filtered and concentrated in vacuo.Purification by flash chromatography (ethyl acetate) afforded compound12 as an oil (5.2 g, 33%). ¹H-NMR (400 MHz, CDCl₃): δ 8.53-8.49 (m, 2H),7.66 (bd, J=8 Hz, 1H), 7.29-7.24 (m, 1H), 3.78 (s, 2H), 3.68 (s, 3H),3.20 (s, 3H).

1-Pyridin-3-yl-hexan-2-one (Compound 13, Scheme 2)

To a solution of anhydrous THF (15 ml) containing compound 12 (1.0 g,5.5 mmol) was added 2.6 ml (6.5 mmol) of n-Buli (2.5 M in hexanes)dropwise at −50° C. under N₂. After the addition, the resulting solutionwas stirred for 30 minutes at −50° C. The mixture was allowed to warm toambient temperature and poured into a NH₄Cl solution (10 g/50 ml H₂O, 0°C.). Ethyl acetate was added and the organic layer was washed with a 5%NaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresulting residue was purified by flash chromatography (ethyl acetate)to give compound 13 as an oil (0.21 g, 25%). ¹H-NMR (400 MHz, CDCl₃): δ8.50 (dd, J=5 Hz, 2 Hz, 1H), 8.45 (d, J=2 Hz, 1H), 7.54 (dt, J=8 Hz, J=2Hz, 1H), 7.29-7.24 (m, 1H), 3.70 (s, 2H), 2.50 (t, J=7 Hz, 2H),1.62-1.53 (m, 2H), 1.34-1.24 (m, 2H), 0.9 (bt, J=7 Hz, 3H).

1-Dimethylamino-2-pyridin-3-yl-hept-1-en-3-one. (Compound 14, Scheme 2)

A solution of 13 (2.0 g, 11 mmol) and DMFDMA (2.5 ml, 14.6 mmol) in dryt-BuOH was refluxed for 18 hours under N₂. The solution was allowed toattain room temperature and subsequently concentrated in vacuo. Theresulting residue was purified by flash chromatography (ethyl acetate)to give compound 14 as an oil (1.85 g, 62%). ¹H-NMR (400 MHz, CDCl₃): δ8.51 (dd, J=5 Hz, 2 Hz, 1H), 8.45 (d, J=2 Hz, 1H), 7.66 (s, 1H), 7.53(dt, J=8 Hz, J=2 Hz, 1H), 7.28-7.24 (m, 1H), 2.72 (bs, 6H), 2.20 (t, J=7Hz, 2H), 1.54-1.46 (m, 2H), 1.26-1.16 (m, 2H), 0.9 (bt, J=7 Hz, 3H).

3-(4-Butyl-1H-pyrazol-3-yl)-pyridine (Compound 15, Scheme 2)

Compound 14 (0.95 g, 4 mmol) and 0.46 ml hydrazine hydrate (9.4 mmol)were dissolved in anhydrous ethanol (25 ml) and heated to reflux for 2hours. The mixture was cooled and concentrated in vacuo. The resultingresidue was purified by flash chromatography (ethyl acetate) to givecompound 15. (amorphous, 0.7 g, 85%). ¹H-NMR (200 MHz, CDCl₃): δ 8.65(d, J=2 Hz, 1H), 8.52 (dd, J=5 Hz, 2 Hz, 1H), 7.72-7.67 (m, 2H),7.35-7.31 (m, 1H), 2.82 (t, J=7 Hz, 2H), 1.70-1.62 (m, 2H), 1.42-1.33(m, 2H), 0.9 (bt, J=7 Hz, 3H).

3-(4-Butyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 16, Scheme 2)

Iodomethane (0.9 ml, 14 mmol) was added to a solution of 15 (600 mg, 3mmol) in acetone (50 ml). After heating for 12 hours, the reactionmixture was cooled and the precipitated crystals were filtered, washedwith diethyl ether and dried to afford the corresponding pyridiniumiodide derivative. To a cooled (−30° C.) suspension of this pyridiniumiodide derivative in MeOH (100 ml), sodium borohydride (0.5 g, 18.9mmol) was added in small portions. The mixture was allowed to warm toambient temperature and poured into a saturated NH₄Cl solution (0° C.).The solvent was (partly) removed under reduced pressure. Ethyl acetatewas added and the organic layer was washed with a concentrated NaHCO₃solution, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresulting residue was purified by flash chromatography(MeOH/triethylamine 97/3) to afford the title compound 16 (amorphous,500 mg, 70% (overall)). ¹H-NMR (400 MHz, CDCl₃): δ 7.40 (bs, 1H),5.78-5.74 (bs, 1H), 3.15-3.05 (m, 2H), 2.71 (bt, J=7 Hz, 2H), 2.56 (t,J=6 Hz, 2H), 2.43 (s, 3H), 2.38-2.32 (m, 2H), 1.68-1.60 (m, 2H),1.43-1.36 (m, 2H), 0.96 (t, J=7 Hz, 3H).

3-(4-Methylsulfanyl-1H-pyrazol-3-yl)-pyridine (Compound 21A, Scheme 3)

To a solution of anhydrous THF (150 ml) containing compound 20A (3.0 g,13.4 mmol, prepared accordingly to Bioorganic & Medicinal Chemistry, 4,1996, 227-237) was added 2.1 eq n-BuLi (11.2 ml, 2.5 M in hexane)dropwise at −78° C. under N₂. After the addition, the resulting solutionwas stirred for 2 hours at −78° C. At this temperature 1.1 eqmethyldisulfanyl methane (1.33 ml) was added and the resulting solutionwas stirred for 1 hour at −78° C. and subsequently allowed to warm toambient temperature overnight. Then the mixture was quenched with asaturated NH₄Cl solution at 0° C. and concentrated in vacuo. Ethylacetate was added and the organic layer was washed with 5% NaHCO₃, dried(Na₂SO₄), filtered and concentrated in vacuo. Purification by flashchromatography (ethyl acetate) afforded compound 21A (oil, 1.71 g, 67%).¹H-NMR (200 MHz, CDCl₃): δ 9.18 (d, J=2 Hz, 1H), 8.60 (dd, J=5 Hz, 2 Hz,1H), 8.28 (dt, J=8 Hz, 2 Hz, 1H), 7.70 (s, 1H), 7.42-7.33 (m, 1H), 2.38(s, 3H).

3-(4-Methylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22A, Scheme 3)

2.5 eq iodomethane (1.39 ml, 22.37 mmol) were added to a solution of 21A(1.71 g, 8.95 mmol) in acetone (100 ml) and the mixture was stirred for18 hours. The precipitated crystals were filtered, washed with diethylether and dried to afford the corresponding pyridinium iodidederivative. To a cooled (−30° C.) suspension of this pyridinium iodidederivative in MeOH (100 ml), sodium borohydride (1.35 g, 35.5 mmol) wasadded in small portions. The mixture was allowed to warm to ambienttemperature and poured into a saturated NH₄Cl solution (0° C.). Thesolvent was (partly) removed under reduced pressure. Ethyl acetate wasadded and the organic layer was washed with a concentrated NaHCO₃solution, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresulting residue was purified by flash chromatography (MeOH) to affordthe title compound 22A. (solid, 1.39 g, 74% (overall)). mp 131.5° C.LCMS (method A); R_(t): 0.96 min, ([M+H]⁺=210). ¹H-NMR (400 MHz, CDCl₃):δ 7.52 (s, 1H), 6.56-6.46 (bs, 1H), 3.40-3.36 (m, 2H), 2.62 (bt, J=6 Hz,2H), 2.46 (s, 3H), 2.45-2.38 (m, 2H), 2.30 (s, 3H).

3-[4-(4,4,4-trifluoro-butylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22B, Scheme 4)

A 60% dispersion of NaH in mineral oil (0.54 g, 13.64 mmol) was added toa solution of anhydrous THF (100 ml) containing compound 20A (2.79, 12.4mmol) under N₂. The resulting mixture was stirred for 2 hours at roomtemperature and subsequently treated with 13.64 mmol (2.41 ml) of(2-Chloromethoxy-ethyl)-trimethylsilane (SEM-Cl). The resulting mixturewas stirred for 18 hours at room temperature. Ethyl acetate was added tothe mixture and the organic layer was washed three times with asaturated NaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated.The resulting residue was purified by flash chromatography (diethylether/PE 1/1) to give a mixture of 27A (major component) and 27B as anoil (3.19 g, 73%). Carefully controlled purification by flashchromatography (diethyl ether/PE 1/1) gave 27B and subsequently 27A.Compound 27B (oil). ¹H-NMR (400 MHz, CDCl₃): δ 9.15 (d, J=2 Hz, 1H),8.60 (dd, J=5 Hz, 2 Hz, 1H), 8.20 (dt, J=8 Hz, 2 Hz, 1H), 7.71 (s, 1H),7.38-7.34 (m, 1H), 5.44 (s, 2H), 3.64 (t, J=8 Hz, 2H), 0.94 (bt, J=8 Hz,2H), 0.02 (s, 9H). Compound 27A (oil). ¹H-NMR (400 MHz, CDCl₃): δ 8.90(d, J=2 Hz, 1H), 8.75 (dd, J=5 Hz, 2 Hz, 1H), 7.96 (dt, J=8 Hz, 2 Hz,1H), 7.63 (s, 1H), 7.47-7.42 (m, 1H), 5.34 (s, 2H), 3.70 (t, J=8 Hz,2H), 0.92 (bt, J=8 Hz, 2H), 0.02 (s, 9H). NOESYPHSW and HMBCGP analyseswere used to confirm both compounds.

To a solution of anhydrous THF (50 ml) containing a mixture of 27A/B(0.92 g, 2.6 mmol) was added 1.14 ml (1.1 eq) of n-BuLi (2.5 M inhexane) dropwise (−78° C. under N₂). After the addition, the resultingsolution was stirred for 60 minutes at −78° C. At this temperature,sulfur powder (2.6 mmol, 0.083 g) was added and the reaction mixture wasstirred for another 2 hours (−78° C.). The reaction was monitored bythin-layer chromatography. After the addition of4-bromo-1,1,1-trifluoro-butane (1.1 eq, 0.54 ml), the mixture wasallowed to warm to ambient temperature (overnight) and poured into asaturated NH₄Cl solution (0° C.). The solvent was (partly) removed underreduced pressure. Ethyl acetate was added and the organic layer waswashed with a concentrated NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting residue was purified by flashchromatography (diethyl ether/PE 1/1)) to afford a mixture of(predominantly) 28A and 28B. (oil, 0.49 g, 45%). ¹H-NMR (data of 28A aredescribed, 400 MHz, CDCl₃): δ 8.80 (d, J=2 Hz, 1H), 8.70 (dd, J=5 Hz, 2Hz, 1H), 7.96 (dt, J=8 Hz, 2 Hz, 1H), 7.68 (s, 1H), 7.48-7.43 (m, 1H),5.35 (s, 2H), 3.72 (bt, J=8 Hz, 2H), 2.58 (t, J=7 Hz, 2H), 2.10-1.97 (m,2H), 1.71-1.59 (m, 2H), 0.93 (bt, J=8 Hz, 2H), 0.00 (s, 9H).

To a solution of anhydrous THF (20 ml) containing a mixture of 28A/B(0.49 g, 1.18 mmol) was added 3.54 ml (3.0 eq) of TBAF (1.0 M in THF)under N₂. After the addition, the resulting solution was refluxed for 18hours and subsequently concentrated in vacuo. Ethyl acetate was addedand the organic layer was washed with a concentrated NaHCO₃ solution,dried (Na₂SO₄), filtered and concentrated in vacuo. The resultingresidue was purified by flash chromatography (diethyl ether) to afford3-[4-(4,4,4-Trifluoro-butylsulfanyl)-1H-pyrazol-3-yl]-pyridine (21B).(oil, 0.32 g, 95%). ¹H-NMR (400 MHz, CDCl₃): δ 9.20 (d, J=2 Hz, 1H),8.65 (dd, J=5 Hz, 2 Hz, 1H), 8.28 (dt, J=8 Hz, 2 Hz, 1H), 7.73 (s, 1H),7.42-7.37 (m, 1H), 2.61 (t, J=7 Hz, 2H), 2.19-2.08 (m, 2H), 1.75-1.65(m, 2H).

Compound 21B (0.3 g, 1.49 mmol) was converted to compound 22B, using themethodology described for the conversion of 21A to 22A. Yield 0.131 g(amorphous, 72% overall). LCMS (method A); R_(t): 1.64 min,([M+H]⁺=306). ¹H-NMR (400 MHz, CDCl₃): δ 7.57 (s, 1H), 6.67-6.60 (bs,1H), 3.43-3.39 (m, 2H), 2.71-2.62 (m, 4H), 2.49 (s, 3H), 2.48-2.43 (m,2H), 2.28-2.19 (m, 2H), 1.81-1.75 (m, 2H).

bis-[3-(1-Methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-yl)-2-sulfanylethyl]-methane(Compound 22C, Scheme 7)

A 60% dispersion of NaH in mineral oil (0.73 g, 18.3 mmol) was added toa solution of anhydrous THF (100 ml) containing compound 20A (3.71, 16.6mmol) under N₂. The resulting mixture was stirred for 2 hours at roomtemperature and subsequently treated with 18.3 mmol (2.33 ml)Phenylsulfonyl chloride. The resulting mixture was stirred for 18 hoursat room temperature. Ethyl acetate was added to the mixture and theorganic layer was washed three times with a saturated NaHCO₃ solution,dried (Na₂SO₄), filtered and concentrated. The resulting residue waspurified by flash chromatography (diethyl ether to afford3-(1-phenylsulfonyl-4-bromo-1H-pyrazol-3-yl)-pyridine (36A). (TLC ethylacetate R_(f) 0.7) (amorphous, 5.34 g, 89%). ¹H-NMR (400 MHz, CDCl₃): δ9.1 (d, J=2 Hz, 1H), 8.65 (dd, J=5 Hz, 2 Hz, 1H), 8.24 (s, 1H), 8.16(dt, J=8 Hz, 2 Hz, 1H), 8.10-8.05 (m, 2H), 7.70 (bt, J=7 Hz, 2H),7.62-7.56 (m, 2H), 7.39-7.34 (m, 1H).

To a degassed solution of xylene (20 ml) containing 36 (0.7 g, 1.92mmol), were added 0.45 eq (0.12 ml, 0.86 mmol) of pentane-1,5-di-thioland 0.5 eq of K₂CO₃ (0.137 g, 0.96 mmol). The resulting mixture wasstirred for another 2 hours under N₂. Successively were added 0.192 mmolof Pd₂(dba)₃ (176 mg) and 0.384 mmol of Xantphos (222 mg). After theaddition, the resulting solution was refluxed for 18 hours under N₂.After cooling to room temperature, the mixture was diluted with ethylacetate, washed three times with a saturated NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated. The resulting residue was purifiedby flash chromatography (ethyl acetate) to afford compound 37 as an oil(0.46 g, 68%). (TLC ethyl acetate R_(f) 0.29).

Compound 37 (0.46 g, 0.65 mmol), 0.7 g KOH and 1 ml NH₂NH₂.H₂O werecombined in diethylene glycol (10 ml) and warmed to reflux for 1 hourunder N₂. The mixture was cooled, concentrated and re-dissolved in MeOH.Filtration over 5 g of SCX-2 (MeOH followed by 1 N NH₃/MeOH) andsubsequent purification by flash chromatography (ethyl acetate) affordedbis-[3-pyridin-3-yl-1H-pyrazol-4-yl)-2-sulfanylethyl]-methane as thedeprotected analog of 37 (amorphous, 0.23 g, 83%). ¹H-NMR (400 MHz,CDCl₃): δ 9.15 (d, J=2 Hz, 2H), 8.57 (dd, J=5 Hz, 2 Hz, 2H), 8.31 (dt,J=8 Hz, 2 Hz, 2H), 7.66 (s, 2H), 7.36-7.32 (m, 2H), 2.50-2.42 (m, 4H),1.34-1.26 (m, 6H).

The deprotected analog of compound 37 (0.23 g, 0.54 mmol) was convertedto compound 22C, using the methodology described for the conversion of21 A to 22A. Yield 0.2 g (oil, 80% overall). LCMS (method A); R_(t):1.66 min, ([M+H]⁺=459). ¹H-NMR (400 MHz, CDCl₃): δ 7.50 (s, 2H),6.92-6.85 (bs, 2H), 3.90-3.80 (m, 4H), 3.07 (bt, J=7 Hz, 4H), 2.77 (s,6H), 2.66-2.54 (m, 8H), 1.54-1.43 (m, 6H).

3-(4-Ethylsulfanyl-1H-pyrazol-3-yl)-pyridine (Compound 21D)

Compound 21D was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using ethyldisulfanyl-ethane asthe disulfide and 3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A).

Yield: 76%. (oil). LCMS (Method A); R_(t): 1.56 min, ([M+H]⁺=206).¹H-NMR (200 MHz, CDCl₃): δ 9.11 (d, J=2 Hz, 1H), 8.64 (dd, J=5 Hz, 2 Hz,1H), 8.18 (dt, J=8 Hz, 2 Hz, 1H), 7.71 (s, 1H), 7.39-7.35 (m, 1H), 2.64(q, J=7 Hz, 2H), 1.26 (t, J=7 Hz, 3H).

3-(4-Ethylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22D)

Compound 22D was prepared from compound 21D following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).

Yield: 73% (solid). mp 95-97° C. LCMS (method A); R_(t): 1.15 min,([M+H]⁺=224). ¹H-NMR (mixture of rotational isomers (3/1), major onedescribed, 400 MHz, CDCl₃): δ 7.53 (s, 1H), 6.55-6.46 (bs, 1H),3.40-3.37 (m, 2H), 2.67-2.60 (m, 4H), 2.46 (s, 3H), 2.43-2.36 (m, 2H),1.19 (3H).

3-(4-Propylsulfanyl-1H-pyrazol-3-yl)-pyridine (Compound 21E)

Compound 21E was prepared following the procedure as described for thesynthesis of compound 21A using (see scheme 3)1-propyldisulfanyl-propane as the disulfide and3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A). (flashchromatography conditions ethyl acetate/diethyl ether 5/1).

Yield: 76%. (oil). ¹H-NMR (200 MHz, CDCl₃): δ 9.20 (d, J=2 Hz, 1H), 8.60(dd, J=5 Hz, 2 Hz, 1H), 8.31 (dt, J=8 Hz, 2 Hz, 1H), 7.68 (s, 1H),7.39-7.35 (m, 1H), 2.56 (t, J=7 Hz, 2H), 1.54-1.43 (m, 2H), 0.90 (t, J=7Hz, 3H).

3-(4-Propylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22E)

Compound 22E was prepared compound from 21E following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).Yield: 77% (solid). mp 111° C. LCMS (method A); R_(t): 1.39 min,([M+H]⁺=238). ¹H-NMR (mixture of rotational isomers 8/1), major onedescribed, 400 MHz, CDCl₃): δ 7.55 (s, 1H), 6.61-6.55 (bs, 1H),3.43-3.39 (m, 2H), 2.68-2.60 (m, 4H), 2.48 (s, 3H), 2.46-2.39 (m, 2H),1.58 (dq, J=7 Hz, 7 Hz, 2H), 0.98 (t, J=7 Hz, 3H).

3-(4-Butylsulfanyl-1H-pyrazol-3-yl)-pyridine (Compound 21F)

Compound 21F was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using 1-butyldisulfanyl-butaneas the disulfide and 3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B).(flash chromatography conditions ethyl acetate/diethyl ether 3/1).

Yield: 18.4%. (oil). ¹H-NMR (200 MHz, CDCl₃): δ 9.20 (d, J=2 Hz, 1H),8.60 (dd, J=5 Hz, 2 Hz, 1H), 8.31 (dt, J=8 Hz, 2 Hz, 1H), 7.68 (s, 1H),7.39-7.34 (m, 1H), 2.58 (t, J=7 Hz, 2H), 1.48-1.40 (m, 2H), 1.36-1.25(m, 2H), 0.90 (t, J=7 Hz, 3H).

3-(4-Butylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22F)

Compound 22F was prepared from compound 21F following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).

Yield: 73% (amorphous). Compound 22A was reacted with 1 equivalent offumaric acid in EtOH and concentrated. Recrystallization from EtOH/ethylacetate afforded a solid (free base/fumaric acid 1/1), mp 120-121° C.LCMS (method A); R_(t): 1.16 min, ([M+H]⁺=252).

3-(4-Pentylsulfanyl-1H-pyrazol-3-yl)-pyridine (Compound 21G)

Compound 21G was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using1-pentyldisulfanyl-pentane as the disulfide and3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A).

Yield: 71%. (oil). ¹H-NMR (400 MHz, CDCl₃): δ 9.18 (d, J=2 Hz, 1H), 8.60(dd, J=5 Hz, 2 Hz, 1H), 8.32 (dt, J=8 Hz, 2 Hz, 1H), 7.66 (s, 1H),7.39-7.34 (m, 1H), 2.57 (t, J=7 Hz, 2H), 1.48-1.41 (m, 2H), 1.30-1.14(m, 4H), 0.81 (t, J=7 Hz, 3H).

3-(4-Pentylsulfanyl-1H-pyrazol-3-yl)-1,2,516-tetrahydro-1-methylpyridine(Compound 22G)

Compound 22G was prepared from compound 21G following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).

Yield: 77% (solid). mp 100-101° C. LCMS (method A); R_(t): 1.67 min,([M+H]⁺=266). ¹H-NMR (400 MHz, CDCl₃): δ 7.51 (s, 1H), 6.56-6.47 (bs,1H), 3.40-3.36 (m, 2H), 2.65-2.59 (m, 4H), 2.45 (s, 3H), 2.44-2.38 (m,2H), 1.57-1.47 (m, 4H), 1.39-1.24 (m, 4H) 0.88 (t, J=7 Hz, 3H).

3-(4-Hexylsulfanyl-1H-pyrazol-3-yl)-pyridine (Compound 21H)

Compound 21H was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using 1-hexyldisulfanyl-hexaneas the disulfide and 3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B).

Yield: 37%. (oil). ¹H-NMR (400 MHz, CDCl₃): δ 9.18 (d, J=2 Hz, 1H), 8.62(dd, J=5 Hz, 2 Hz, 1H), 8.31 (dt, J=8 Hz, 2 Hz, 1H), 7.70 (s, 1H),7.40-7.35 (m, 1H), 2.59 (t, J=7 Hz, 2H), 1.50-1.42 (m, 2H), 1.34-1.12(m, 6H), 0.81 (t, J=7 Hz, 3H).

3-(4-Hexylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22H)

Compound 22H was prepared from compound 21H following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).

Yield: 49% (amorphous). LCMS (method A); R_(t): 1.81 min, ([M+H]⁺=280).¹H-NMR (400 MHz, CDCl₃): δ 7.51 (s, 1H), 6.60-6.50 (bs, 1H), 3.40-3.36(m, 2H), 2.65-2.59 (m, 4H), 2.45 (s, 3H), 2.44-2.38 (m, 2H), 1.56-1.48(m, 2H), 1.39-1.20 (m, 6H) 0.88 (t, J=7 Hz, 3H).

3-[4-(3-Phenyl-propylsulfanyl)-1H-pyrazol-3-yl]-pyridine (Compound 21I)

Compound 21I was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using3-phenyl-propyldisulfanyl-3-propylbenzene as the disulfide (preparedaccording to the methodology described in Tetrahedron Letters, 42, 2001,6741-6743) and 3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A).(conditions flash chromatography (ethyl acetate)) Yield: 22% (oil).¹H-NMR (400 MHz, CDCl₃): δ 9.18 (d, J=2 Hz, 1H), 8.62 (dd, J=5 Hz, 2 Hz,1H), 8.31 (dt, J=8 Hz, 2 Hz, 1H), 7.69 (s, 1H), 7.40-7.36 (m, 1H), 7.24(bt, J=7 Hz, 2H), 7.17 (bt, J=7 Hz, 1H), 7.04 (bd, J=7 Hz, 2H),2.65-2.57 (m, 4H), 1.84-1.75 (m, 2H).

3-[4-(3-Phenyl-propylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22I)

Compound 22I was prepared from compound 21I following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).

Yield: 59% (amorphous). ¹H-NMR (400 MHz, CDCl₃): δ 7.51 (s, 1H),7.30-7.22 (m, 2H), 7.21-7.12 (m, 3H), 6.66-6.46 (bs, 1H), 3.39-3.34 (m,2H), 2.70-2.55 (m, 6H), 2.44 (s, 3H), 2.43-2.36 (m, 2H), 1.89-1.80 (m,2H).

3-[4-(4,4-Difluoro-but-3enylsulfanyl)-1H-pyrazol-3-yl]-pyridine(Compound 21J)

Compound 21J was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using4-(4,4-difluoro-but-3-enyldisulfanyl)-1,1-difluoro-but-1-ene as thedisulfide (Tetrahedron Letters, 42, 2001, 6741-6743) and3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A). (conditions flashchromatography (ethyl acetate)) Yield: 58% (oil). ¹H-NMR (400 MHz,CDCl₃): δ 9.18 (d, J=2 Hz, 1H), 8.62 (dd, J=5 Hz, 2 Hz, 1H), 8.31 (dt,J=8 Hz, 2 Hz, 1H), 7.72 (s, 1H), 7.42-7.36 (m, 1H), 4.19-4.06 (m, 1H),2.59 (t, J=7 Hz, 2H), 2.18-2.09 (m, 2H).

3-[4-(4,4-Difluoro-but-3enylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22J)

Compound 22J was prepared from compound 21H following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).Yield: 90% (amorphous). ¹H-NMR (400 MHz, CDCl₃): δ 7.54 (s, 1H),6.68-6.44 (bs, 1H), 4.27-4.15 (m, 1H), 3.40-3.36 (m, 2H), 2.66-2.60 (m,4H), 2.47 (s, 3H), 2.45-2.38 (m, 2H), 2.22-2.14 (m, 2H).

3-[4-(3-Phenyl-allylsulfanyl)-1H-pyrazol-3-yl]-pyridine (Compound 21 K)

Compound 21K was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using3-phenyl-allyldisulfanyl-3-alkylbenzene as the disulfide (TetrahedronLetters, 42, 2001, 6741-6743) and 3-(4-bromo-1H-pyrazol-3-yl)-pyridine(compound 20A). (conditions flash chromatography (ethyl acetate)).Yield: 22%. (oil), (TLC ethyl acetate R_(f) 0.45).

3-[4-(3-Phenyl-allylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22K)

Compound 22K was prepared from compound 21K following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).

Yield: 72% (amorphous). ¹H-NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H),7.30-7.18 (m, 5H), 6.70-6.20 (bs, 1H), 6.20-6.07 (m, 2H), 3.37 (d, J=7Hz, 2H), 3.33-3.28 (m, 2H), 2.54 (bt, J=7 Hz, 2H), 2.40 (s, 3H),2.39-2.30 (m, 2H).

3-[4-Pent-4-enylsulfanyl)-1H-pyrazol-3-yl]-pyridine (Compound 21L)

Compound 21L was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using5-pent-4-enyldisulfanyl-pent-1-ene as the disulfide (TetrahedronLetters, 42, 2001, 6741-6743) and 3-(4-iodo-1H-pyrazol-3-yl)-pyridine(compound 20B). (conditions flash chromatography (ethyl acetate)) Yield:28%. (oil). LCMS (method A); R_(t): 2.21 min, ([M+H]⁺=246). ¹H-NMR (400MHz, CDCl₃): δ 9.20 (d, J=2 Hz, 1H), 8.62 (dd, J=5 Hz, 2 Hz, 1H), 8.31(dt, J=8 Hz, 2 Hz, 1H), 7.71 (s, 1H), 7.41-7.35 (m, 1H), 5.73-5.59 (m,2H), 4.97-4.89 (m, 2H), 2.59 (t, J=7 Hz, 2H), 2.10-2.03 (m, 2H),1.61-1.54 (m, 2H).

3-[4-Pent-4-enylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22L)

Compound 22L was prepared from compound 21L following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).Yield: 61% (amorphous). LCMS (method A); R_(t): 1.84 min, ([M+H]⁺=264).¹H-NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 6.70-6.40 (bs, 1H), 5.81-5.68(m, 1H), 5.04-4.94 (m, 2H), 3.40-3.36 (m, 2H), 2.66-2.57 (m, 4H), ‘2.45(s, 3H), 2.45-2.37 (m, 2H), 2.17-2.09 (m, 2H), 1.66-1.58 (m, 2H).

3-[4-(Furan-2-ylmethylsulfanyl)-1H-pyrazol-3-yl]-pyridine (Compound 21M)

Compound 21M was prepared following the procedure as described for thesynthesis of compound 21A (see scheme 3) using difurfuryl-disulfide and3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (conditions flashchromatography (ethyl acetate)) Yield: 54%. (oil). ¹H-NMR (200 MHz,CDCl₃): δ 9.20 (d, J=2 Hz, 1H), 8.59 (dd, J=5 Hz, 2 Hz, 1H), 8.20 (dt,J=8 Hz, 2 Hz, 1H), 7.54 (s, 1H), 7.38-7.32 (m, 1H), 7.21-7.19 (m, 1H),6.16-6.12 (m, 1H), 5.88-5.84 (m, 1H), 3.75 (s, 2H).

3-[4-(Furan-2-yl-methylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22M)

Compound 22M was prepared from compound 21M following the procedure asdescribed for the synthesis of compound 22A (see Scheme 3). Yield: 65%(amorphous). LCMS (method A); R_(t): 1.04 min, ([M+H]⁺=276). ¹H-NMR (200MHz, CDCl₃): δ 7.36 (s, 1H), 7.33-7.31 (m, 1H), 6.38-6.26 (bs, 1H),6.24-6.20 (m, 1H), 5.93-5.90 (m, 1H), 3.78 (s, 2H), 3.30-3.22 (m, 2H),2.60 (bt, J=7 Hz, 2H), 2.44 (s, 3H), 2.41-2.33 (m, 2H).

3-(4-Benzylsulfanyl-1H-pyrazol-3-yl)-pyridine (Compound 21N)

Compound 21N was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using dibenzyl-disulfide and3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (conditions flashchromatography (ethyl acetate)) Yield: 33%. (oil). ¹H-NMR (400 MHz,CDCl₃): δ 9.0 (d, J=2 Hz, 1H), 8.58 (dd, J=5 Hz, 2 Hz, 1H), 8.10 (dt,J=8 Hz, 2 Hz, 1H), 7.43 (s, 1H), 7.33-7.28 (m, 1H), 7.17-7.11 (m, 3H),7.02-6.96 (m, 2H), 3.72 (s, 2H).

3-(4-Benzylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22N)

Compound 22N was prepared from compound 21N following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).Yield: 48% (amorphous). LCMS (method A); R_(t): 1.55 min, ([M+H]⁺=286).Compound 22N was reacted with 1 equivalent of fumaric acid in EtOH andconcentrated. ¹H-NMR (600 MHz, D₆DMSO): δ 7.63 (s, 1H), 7.28 (t, J=7 Hz,2H), 7.28 (t, J=7 Hz, 2H), 7.24 (bt, J=7 Hz, 1H), 7.17 (bd, J=7 Hz, 2H),6.82-6.79 (bs, 1H), 6.66 (s, 2H), 4.28 (bd, J=15 Hz, 1H), 4.05 (dd, J=16Hz, 6 Hz, 2H), 3.86-3.80 (m, 1H), 3.55-3.50 (m, 1H), 3.18-3.10 (m, 1H),2.94 and 2.93 (2×s, 3H), 2.68-2.46 (m, 2H).

3-[4-(2-Ethoxy-ethylsulfanyl)-1H-pyrazol-3-yl]-pyridine (Compound 21O)

Compound 21O was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using1-ethoxy-2-(2-ethoxy-ethyldisulfanyl)-ethane as the disulfide(Tetrahedron Letters, 42, 2001, 6741-6743) and3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (conditions flashchromatography (ethyl acetate)) Yield: 28%. (oil). LCMS (method A);R_(t): 2.21 min, ([M+H]⁺=246). ¹H-NMR (400 MHz, CDCl₃): δ 9.20 (d, J=2Hz, 1H), 8.62 (dd, J=5 Hz, 2 Hz, 1H), 8.33 (dt, J=8 Hz, 2 Hz, 1H), 7.75(s, 1H), 7.41-7.36 (m, 1H), 3.46 (t, J=7 Hz, 2H), 3.38 (q, J=7 Hz, 2H),2.78 (t, J=7 Hz, 2H), 1.14 (t, J=7 Hz, 3H),

3-[4-(2-Ethoxy-ethylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22O)

Compound 22O was prepared from compound 21O following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).Yield: 63% (amorphous). ¹H-NMR (400 MHz, CDCl₃): δ 7.56 (s, 1H),6.70-6.50 (bs, 1H), 3.55-3.43 (m, 4H), 3.40-3.36 (m, 2H), 2.81 (t, J=7Hz, 2H), 2.61 (bt, J=7 Hz, 2H), 2.46 (s, 3H), 2.44-2.38 (m, 2H), 1.18(t, J=7 Hz, 3H).

3-{4-[2-(2-Methoxy-ethoxy)-ethylsulfanyl]-1H-pyrazol-3-yl}-pyridine(Compound 21P)

Compound 21P was prepared following the procedure as described for thesynthesis of compound 21^(a) (see Scheme 3) using1-methoxy-2-{2-[2-((2-methoxy-ethoxy)-ethyldisulfanyl]-ethoxy}-ethane asthe disulfide (Tetrahedron Letters, 42, 2001, 6741-6743) and3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (conditions flashchromatography (ethyl acetate)) Yield: 36%. (oil). ¹H-NMR (400 MHz,CDCl₃): δ 9.18 (d, J=2 Hz, 1H), 8.58 (dd, J=5 Hz, 2 Hz, 1H), 8.35 (dt,J=8 Hz, 2 Hz, 1H), 7.78 (s, 1H), 7.39-7.32 (m, 1H), 3.51-3.44 (m, 6H),3.34 (s, 3H), 2.78 (t, J=7 Hz, 2H).

3-[4-[2-(2-Methoxy-ethoxy)-ethylsulfanyl]-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22P)

Compound 22P was prepared from compound 21P following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).Yield: 33% (amorphous). ¹H-NMR (400 MHz, CDCl₃): δ 7.57 (s, 1H),6.74-6.69 (bs, 1H), 3.59-3.51 (m, 8H), 3.38 (s, 3H), 2.83 (t, J=7 Hz,2H), 2.77 (bt, J=7 Hz, 2H), 2.55 (s, 3H), 2.52-2.45 (m, 2H).

3-(4-Allylsulfanyl-1H-pyrazol-3-yl)-pyridine (Compound 21Q)

Compound 21Q was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using 3-allyldisulfanyl-propeneas the disulfide and 3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B).(conditions flash chromatography (ethyl acetate)) Yield: 27%. (oil).¹H-NMR (200 MHz, CDCl₃): δ 9.20 (d, J=2 Hz, 1H), 8.60 (dd, J=5 Hz, 2 Hz,1H), 8.29 (dt, J=8 Hz, 2 Hz, 1H), 7.70 (s, 1H), 7.40-7.36 (m, 1H),5.77-5.66 (m, 1H), 4.94 (bdd, J=11 Hz, 1 Hz, 1H), 4.83 (bdd, J=17 Hz, 1Hz, 1H), 3.19 (bd, J=8 Hz, 2H).

3-(4-Allylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22Q)

Compound 22Q was prepared from compound 21Q following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).Yield: 17% (amorphous). ¹H-NMR (200 MHz, CDCl₃): δ 7.52 (s, 1H),6.62-6.48 (bs, 1H), 5.84-5.74 (m, 1H), 4.98 (bdd, J=11 Hz, 1 Hz, 1H),4.90 (bdd, J=17 Hz, 1 Hz, 1H), 4.00-3.95 (m, 2H), 3.23 (bd, J=8 Hz, 2H),2.61 (bt, J=7 Hz, 2H), 2.46 (s, sH), 2.44-2.39 (m, 2H).

3-(3-Pyridin-3-yl-1H-pyrazol-4-ylsulfanyl)-propionitrile (Compound 21R)

Compound 21R was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using3-(2-cyano-ethyldisulfanyl)-propionitrile as the disulfide and3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (conditions flashchromatography (ethyl acetate)) Yield: 62%. (oil). ¹H-NMR (200 MHz,CDCl₃): δ 9.20 (d, J=2 Hz, 1H), 8.60 (dd, J=5 Hz, 2 Hz, 1H), 8.33 (dt,J=8 Hz, 2 Hz, 1H), 7.82 (s, 1H), 7.43-7.37 (m, 1H), 2.76 (t, J=7 Hz,2H), 2.45 (t, J=7 Hz, 2H).

3-[3-(1-Methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-ylsulfanyl]-propionitrile(Compound 22R)

Compound 22R was prepared from compound 21R following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).Yield: 8% (amorphous). ¹H-NMR (200 MHz, CDCl₃): δ 7.58 (s, 1H),6.60-6.50 (bs, 1H), 3.40-3.36 (m, 2H), 2.79 (t, J=7 Hz, 2H), 2.66 (bt,J=7 Hz, 2H), 2.50 (t, J=7 Hz, 2H), 2.47 (s, 3H), 2.45-2.38 (m, 2H).

3-[4-(3-methyl-butylsulfanyl)-1H-pyrazol-3-yl]-pyridine (Compound 21S)

Compound 21S was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using3-Methyl-1-(3-methyl-butyldisulfanyl)-butane as the disulfide and3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (conditions flashchromatography (ethyl acetate)) Yield: 39%. (oil). ¹H-NMR (200 MHz,CDCl₃): δ 9.18 (d, J=2 Hz, 1H), 8.65 (dd, J=5 Hz, 2 Hz, 1H), 8.35 (dt,J=8 Hz, 2 Hz, 1H), 7.78 (s, 1H), 7.39-7.35 (m, 1H), 2.60 (t, J=7 Hz,2H), 1.65-1.57 (m, 1H), 1.42-1.33 (m, 2H), 0.81 (d, J=7 Hz, 6H).

3-[4-(3-methyl-butylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 22S)

Compound 22S was prepared from compound 21S following the procedure asdescribed for the synthesis of compound 22A (from 21A) (see Scheme 3).Yield: 73% (amorphous). ¹H-NMR (200 MHz, CDCl₃): δ 7.5 (s, 1H),6.60-6.48 (bs, 1H), 3.40-3.36 (m, 2H), 2.66-2.59 (m, 4H), 2.45 (s, 3H),2.44-2.39 (m, 2H), 1.72-1.62 (m, 1H), 1.45-1.39 (m, 2H), 0.86 (d, J=7Hz, 6H).

3-Pyridin-3-yl-pyrazole-1-sulfonic acid dimethylamide (Compound 23,Scheme 3)

Compound 19 (3.0 g, 20.7 mmol) and 2.22 ml of phenylsulfonyl chloride(20.7 mmol) were combined in pyridine (100 ml) and stirred for 18 hoursat reflux. The reaction was concentrated in vacuo. The residue was takenup in ethyl acetate, washed three times with a saturated NaHCO₃solution, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresulting residue was purified by flash chromatography (diethyl ether/PE2/1) to afford the afford compound 23 (amorphous, 2.86 g, 55%). ¹H-NMR(200 MHz, CDCl₃): δ 9.1 (d, J=2 Hz, 1H), 8.6 (dd, J=5 Hz, 2 Hz, 1H),8.16 (dt, J=8 Hz, 2 Hz, 1H), 8.05 (d, J=3 Hz, 1H), 7.39-7.34 (m, 1H),6.75 (d, J=3 Hz, 1H), 3.02 (s, 6H).

5-Butylsulfanyl-3-pyridin-3-yl-pyrazol-1-sulfonic acid dimethylamide(Compound 24, Scheme 3)

To a solution of anhydrous THF (50 ml) containing compound 24 (1.0 g, 4mmol) was added 1 eq of n-BuLi (2.35 ml, 1.7 M in pentane) dropwise at−78° C. under N₂. After the addition, the resulting solution was stirredfor 1 hour at −78° C. At this temperature 1.1 eq1-butyldisulfanyl-butane (0.79 ml) was added and the resulting solutionwas stirred for 1 hour at −78° C. and subsequently allowed to warm toambient temperature overnight. Then the mixture was quenched with asaturated NH₄Cl solution at 0° C. and concentrated in vacuo. Ethylacetate was added and the organic layer was washed with a 5% NaHCO₃solution, dried (Na₂SO₄), filtered and concentrated in vacuo.Purification by flash chromatography (diethyl ether/PE 5/1) to ethylacetate/diethyl ether 1/1) afforded compound 24 (oil, 0.93 g, 70%).¹H-NMR (200 MHz, CDCl₃): 9.1 (d, J=2 Hz, 1H), 8.6 (dd, J=5 Hz, 2 Hz,1H), 8.15 (dt, J=8 Hz, 2 Hz, 1H), 7.39-7.34 (m, 1H), 6.50 (s, 1H), 3.02(s, 6H), 3.02 (t, J=7 Hz, 2H), 1.82-1.67 (m, 2H), 1.60-1.42 (m, 2H),0.97 (t, J=7 Hz, 3H).

3-(5-Butylsulfanyl-1H-pyrazol-3-yl)-pyridine (Compound 25, Scheme 3)

Compound 24 (0.92 g, 2.71 mmol) was dissolved in 50 ml of n-BuOH. Tothis solution was added 2 g of KOH dissolved in 50 ml of H₂O and thereaction mixture was stirred for 18 hours at room temperature under N₂.The reaction mixture was concentrated in vacuo. The resulting residuewas taken up in ethyl acetate, washed with a 5% NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo. Purification by flashchromatography (diethyl ether/PE 4/1) afforded compound 25 (amorphous,0.44 g, 70%). (TLC ethyl acetate R_(f) 0.34).

3-(5-Butylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 26, Scheme 3)

Compound 26 was prepared following the procedure as described for thesynthesis of compound 22A (from 21A).

Yield: 70% (amorphous). ¹H-NMR (200 MHz, CDCl₃): δ 6.27 (s, 1H),6.22-6.18 (bs, 1H), 3.31-3.27 (m, 2H), 2.82 (t, J=7 Hz, 2H), 2.58 (bt,J=7 Hz, 2H), 2.44 (s, 3H), 2.39-2.32 (m, 2H), 1.62-1.54 (m, 2H),1.44-1.37 (m, 2H), 0.86 (t, J=7 Hz, 3H).

3-[4-(3-Phenyl-propoxy)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 33A, Scheme 5)

A 60% dispersion of NaH in mineral oil (3 g, 1.1 eq) was added to asolution of anhydrous THF (100 ml) containing compound 20B (18.36 g,68.74 mmol) under N₂. The resulting mixture was stirred for 2 hours atroom temperature and subsequently treated with 13.37 ml (1.1 eq) of(2-chloromethoxy-ethyl)-trimethylsilane (SEM-Cl). The resulting mixturewas stirred for 18 hours at room temperature. Ethyl acetate was added tothe mixture and the organic layer was washed three times with asaturated NaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated.The resulting residue was purified by flash chromatography (diethylether/PE 1/1) to give a (variable) mixture of 29A and 29B as an oil(23.09 g, 83%). ¹H-NMR (400 MHz, CDCl₃): The NMR shows great resemblancewith the NMR of the mixture of 27A/B (see Scheme 4), major isomer(presumably 29A) is given: δ 9.15 (d, J=2 Hz, 1H), 8.65 (dd, J=5 Hz, 2Hz, 1H), 8.17 (dt, J=8 Hz, 2 Hz, 1H), 7.74 (s, 1H), 7.39-7.34 (m, 1H),5.46 (s, 2H), 3.71-3.62 (m, 4H, both isomers), 0.98-0.84 (m, 4H, bothisomers), 0.02 (both isomers, Si(CH₃)₃).

To a solution of anhydrous THF (250 ml) containing a mixture of 29A/B(10 g, 25 mmol) was added 10.5 ml (1.1 eq) of n-BuLi (2.5 M in hexane)dropwise (−78° C. under N₂). After the addition, the resulting solutionwas stirred for 60 minutes at −78° C. At this temperature, trimethylborate (3 eq, 8.50 ml) was added (dropwise in 15 minutes) and thereaction mixture was stirred for another 2 hours at −78° C. The reactionmixture was then allowed to warm to ambient temperature (overnight).

The temperature of the reaction mixture was lowered to −10° C. and 2.2ml (1.5 eq) of acetic acid was added. Subsequently, 1.1 eq of a 30% H₂O₂solution (2.93 ml) was added dropwise, while keeping the temperature<−5° C. The mixture was allowed to warm to ambient temperature andstirred for another 4 hours. To the reaction mixture was added 10 ml ofH₂O and subsequently ethyl acetate (500 ml). The organic layer waswashed with a 5% NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting residue was purified by flashchromatography (diethyl ether followed by ethyl acetate) to afford3-pyridin-3-yl-1-(2-trimethylsilanyl-1-ethoxymethyl)-1H-pyrazol-4-ol(30), as a (variable) mixture of the SEM protected product isomers.(amorphous, 2.9 g, 40%). ¹H-NMR (400 MHz, CDCl₃, mixture of isomers˜1/1): δ 9.22 and 8.90 (2×bs, 1H), 8.47-8.18 (m, 2H), 7.45-7.34 (m, 1H),7.36 and 7.31 (2×s, 1H), 5.36 and 5.35 (2×s, 2H), 3.74-3.69 and3.64-3.59 (2×m, 2H), 0.99-0.90 (m, 2H), 0.02 and 0.01 (2×s, 9H)

To a solution of anhydrous DMF (50 ml) containing compound 30 (2.03 g,6.98 mmol) were added 1.5 eq of K₂CO₃ (1.45 g) and the mixture wasstirred for 1 hour under N₂. After the addition of 3-bromo-propylbenzene(1.1 eq, 1.17 ml), the resulting solution was stirred for 18 hours at45° C. and allowed to reach ambient temperature. Ethyl acetate was addedand the organic layer was washed with a concentrated NaHCO₃ solution,dried (Na₂SO₄), filtered and concentrated in vacuo. The resultingresidue was purified by flash chromatography (diethyl ether) to afford31A as mixture of SEM isomers. (oil, 1.92 g, 67%). ¹H-NMR (400 MHz,CDCl₃, major isomer is given): δ 8.96 (d, J=2 Hz, 1H), 8.61 (dd, J=5 Hz,2 Hz, 1H), 8.05 (dt, J=8 Hz, 2 Hz, 1H), 7.42-7.39 (m, 1H), 7.39 (s, 1H),7.30-7.14 (m, 5H), 5.37 (s, 2H), 3.98 (t, J=7 Hz, 2H), 3.74-3.69 (m,2H), 2.74 (t, J=7 Hz, 2H), 2.10-2.02 (m, 2H), 0.98-0.92 (m, 2H), 0.01(s, 9H).

To a solution of anhydrous THF (50 ml) containing 31A (1.93 g, 4.71mmol) was added 14.16 ml (3.0 eq) of TBAF (1.0 M in THF) under N₂. Afterthe addition, the resulting solution was refluxed for 18 hours andsubsequently concentrated in vacuo. Ethyl acetate was added and theorganic layer was washed with a concentrated NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting residue waspurified by flash chromatography (ethyl acetate) to afford the desired3-[4-(3-phenyl-propoxy)-1H-pyrazol-3-yl]-pyridine (32A). (oil, 1.32 g,73%). ¹H-NMR (400 MHz, CDCl₃): δ 9.15 (d, J=2 Hz, 1H), 8.54 (dd, J=5 Hz,2 Hz, 1H), 8.24 (dt, J=8 Hz, 2 Hz, 1H), 7.35-7.31 (m, 1H), 7.30-7.25 (m,2H), 7.22-7.17 (m, 3H), 3.96 (t, J=7 Hz, 2H), 2.83 (t, J=7 Hz, 2H),2.19-2.11 (m, 2H)

Compound 32A (0.3 g, 1.49 mmol) was converted to compound the titlecompound3-[4-(3-phenyl-propoxy)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(33A), using the methodology described for the conversion of 21A to 22A(see Scheme 3).

Yield: 70% (amorphous, 72%). LCMS (method A); R_(t): 1.52 min,([M+H]⁺=298). ¹H-NMR (400 MHz, CDCl₃): δ 7.31-7.25 (m, 2H), 7.22-7.17(m, 3H), 7.16-7.11 (bs, 1H), 6.62-6.44 (bs, 1H), 3.87 (t, J=7 Hz, 2H),3.41-3.36 (m, 2H), 2.79 (t, J=7 Hz, 2H), 2.58 (t, J=7 Hz, 2H), 2.44 (s,3H), 2.42-2.35 (m, 2H), 2.11-2.04 (m, 2H).

3-(4-Hexyloxy-1H-pyrazol-3-yl]-1,2,516-tetrahydro-1-methylpyridine(Compound 33B, Scheme 6)

Compound 29A/B was converted to3-(4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(compound 34A/B), using the methodology described for the conversion of21A to 22A (see Scheme 3). Yield: 47%.(amorphous). LCMS (method A);R_(t): 2.66 min, ([M+H]⁺=420) and R_(t): 2.74 min, ([M+H]⁺=420).

A mixture of compound 34A/B (0.75 g, 1.79 mmol), CuI (34 mg, 0.179mmol), Cs₂CO₃ (1.18 g, 3.58 mmol), 1,10-phenanthroline (0.07 g, 0.358mmol) and 1-hexanol (5 ml, 40 mmol) was heated at 140° C. for 18 hours(under air).

The mixture was cooled to room temperature. Ethyl acetate was added andthe organic layer was washed met a 5% NaHCO₃ solution, dried (Na₂SO₄),filtered and concentrated in vacuo. The resulting residue was purifiedby flash chromatography (ethyl acetate/PE 1:1) to afford compound 35A asan oil (0.24 g, 34%). LCMS (Method A); R_(t): 2.50 min,([M+H]⁺=394).(TLC ethyl acetate/PE 1/1, R_(f) 0.07).

To a solution of anhydrous THF (20 ml) containing a mixture of 35A (0.24g, 0.6 mmol) was added 1.52 ml (2.5 eq) TBAF (1.0 M in THF) under N₂.After the addition, the resulting solution was refluxed for 18 hours andsubsequently concentrated in vacuo. Ethyl acetate was added and theorganic layer was washed with a concentrated NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting residue waspurified by flash chromatography (ethyl acetate/MeOH (1/1)) to affordthe title compound 33B. (oil, 0.12 g, 75%). LCMS (Method A); R_(t): 1.99min, ([M+H]⁺=264).

Compound 33B was reacted with 1 equivalent of fumaric acid in EtOH andconcentrated (amorphous). ¹H-NMR (600 MHz, D₆DMSO): δ 7.50 (bs, 1H),6.58 (s, 2H), 6.50 (bs, 1H), 3.88 (t, J=7 Hz, 2H), 3.75 (bs, 2H), 3.02(bt, J=7 Hz, 2H), 2.69 (s, 3H), 2.48-2.42 (m, 2H), 1.75-1.67 (m, 2H),1.45-1.38 (m, 2H), 1.36-1.28 (m, 4H), 0.89 (t, J=7 Hz, 3H).

3-(4-Butyloxyy-1H-pyrazol-3-yl)-pyridine (Compound 32C)

Compound 32C was prepared following the procedure as described for thesynthesis of compound 32A (see Scheme 5) using 1-bromo-butane as thealkyl halogenide and3-pyridin-3-yl-1-(2-trimethylsilanyl-1-ethoxymethyl)-1H-pyrazol-4-ol(30). Work-up and flash chromatography (ethyl acetate/diethyl ether 1/1)afforded compound 31C. Yield 30% (oil). ¹H-NMR (major isomer is given,400 MHz, CDCl₃): δ 8.9 (d, J=2 Hz, 1H), 8.6 (dd, J=5 Hz, 2 Hz, 1H), 8.05(dt, J=8 Hz, 2 Hz, 1H), 7.42 (s, 1H), 7.41-7.37 (m, 1H), 5.37 (s, 2H),3.98 (t, J=7 Hz, 2H), 3.74-3.68 (m, 2H), 1.74-1.66 (m, 2H), 1.49-1.39(m, 2H), 0.92 (t, J=7 Hz, 3H), 0.02 (s, 9H).

The mixture of SEM-isomers was deprotected (TBAF/THF) to afford3-(4-butyloxyy-1H-pyrazol-3-yl)-pyridine (32C).

Yield: 70% (amorphous). ¹H-NMR (400 MHz, CDCl₃): δ 9.25 (d, J=2 Hz, 1H),8.53 (dd, J=5 Hz, 2 Hz, 1H), 8.23 (dt, J=8 Hz, 2 Hz, 1H), 7.35-7.31 (m,1H), 7.30 (s, 1H), 3.77 (t, J=7 Hz, 2H), 1.84-1.77 (m, 2H), 1.57-1.47(m, 2H), 0.98 (t, J=7 Hz, 3H).

3-(4-Butyloxyy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 33C)

Compound 32C was converted to the title compound (33C), using themethodology described for the conversion of 21A to 22A (see Scheme 3).

Yield: 77% (amorphous). LCMS (method A); R_(t): 1.48 min, ([M+H]⁺=236).¹H-NMR (400 MHz, CDCl₃) δ 7.19 (bs, 1H), 6.52-6.42 (bs, 1H), 3.88 (t,J=7 Hz, 2H), 3.38-3.34 (m, 2H), 2.57 (t, J=7 Hz, 2H), 2.44 (s, 3H),2.41-2.36 (m, 2H), 1.79-1.71 (m, 2H), 1.53-1.43 (m, 2H), 0.97 (t, J=7Hz, 3H).

3-(4-But-3-enyloxy-1H-pyrazol-3-yl)-pyridine (Compound 32D)

Compound 32D was prepared following the procedure as described for thesynthesis of compound 32A (see Scheme 5) using 4-bromo-but-1-ene as thealkyl halogenide and3-pyridin-3-yl-1-(2-trimethylsilanyl-1-ethoxymethyl)-1H-pyrazol-4-ol(30). Work-up and flash chromatography (diethyl ether) afforded compound31 D. Yield 43% (oil, TLC diethyl ether R_(f) 0.37), which wassubsequently deprotected (TBAF/THF) to afford3-(4-but-3-enyloxy-1H-pyrazol-3-yl)-pyridine (32D).

Yield: 75% (amorphous). ¹H-NMR (400 MHz, CDCl₃): δ 9.15 (d, J=2 Hz, 1H),8.58 (dd, J=5 Hz, 2 Hz, 1H), 8.24 (dt, J=8 Hz, 2 Hz, 1H), 7.35-7.30 (m,1H), 7.32 (s, 1H), 5.96-5.85 (m, 1H), 5.22-5.11 (m, 2H), 4.02 (t, J=7Hz, 2H), 2.62-2.55 (m, 2H).

3-(4-But-3-enyloxyy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 33D)

Compound 32D was converted to the title compound (33D), using themethodology described for the conversion of 21A to 22A (see Scheme 3).

Yield: 94%.(amorphous). LCMS (method A); R_(t): 1.33 min, ([M+H]⁺=234).¹H-NMR (400 MHz, CDCl₃): δ 7.20 (bs, 1H), 6.60-6.42 (bs, 1H), 5.94-5.83(m, 1H), 5.19-5.07 (m, 2H), 3.94 (t, J=7 Hz, 2H), 3.38-3.33 (m, 2H),2.59-2.50 (m, 4H), 2.44 (s, 3H), 2.41-2.36 (m, 2H).

3-(4-Heptyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 33E)

A mixture of compound 34A/B (0.75 g, 1.79 mmol) (see Scheme 6), CuI (34mg, 0.179 mmol), Cs₂CO₃ (1.18 g, 3.58 mmol), 1,10-phenanthroline (0.07g, 0.358 mmol) and 1-heptanol (5 ml) was heated at 140° C. for 18 hours(under air).

The mixture was cooled to room temperature. Ethyl acetate was added andthe organic layer was washed with a 5% NaHCO₃ solution, dried (Na₂SO₄),filtered and concentrated in vacuo. The resulting residue was purifiedby flash chromatography (ethyl acetate/PE 1/1) to afford compound 35E(heptyl analogue of 35A, Scheme 6) as an oil (0.22 g, 30%). LCMS (methodA); R_(t): 2.60 min, ([M+H]⁺=408).

To a solution of anhydrous THF (20 ml) containing a mixture of 35E (0.22g, 0.54 mmol) was added 1.35 ml (2.5 eq) of TBAF (1.0 M in THF) underN₂. After the addition, the resulting solution was refluxed for 18 hoursand subsequently concentrated in vacuo. Ethyl acetate was added and theorganic layer was washed with a concentrated NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting residue waspurified by flash chromatography (ethyl acetate/MeOH 1/1) to afford thetitle compound 33E. (oil, 0.08 g, 53%). LCMS (method A); R_(t): 2.23min, ([M+H]⁺=278).

Compound 33E was reacted with 1 equivalent of fumaric acid in EtOH andconcentrated (amorphous). ¹H-NMR (600 MHz, D₆DMSO): δ 7.37 (bs, 1H),6.58 (s, 2H), 6.43 (bs, 1H), 3.84 (t, J=7 Hz, 2H), 3.51 (bs, 2H), 2.77(bt, J=7 Hz, 2H), 2.52 (s, 3H), 2.39-2.33 (m, 2H), 1.72-1.66 (m, 2H),1.45-1.22 (m, 8H), 0.87 (t, J=7 Hz, 3H).

3-(4-Pent-4-enyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 33F)

A mixture of compound 34A/B (0.75 g, 1.79 mmol) (see Scheme 6), CuI (34mg, 0.179 mmol), Cs₂CO₃ (1.18 g, 3.58 mmol), 1,10-phenanthroline (0.07g, 0.358 mmol) and pent-4-en-1-ol (5 ml) was heated at 140° C. for 18hours (under air).

The mixture was cooled to room temperature. Ethyl acetate was added andthe organic layer was washed met a 5% NaHCO₃ solution, dried (Na₂SO₄),filtered and concentrated in vacuo. The resulting residue was purifiedby flash chromatography (ethyl acetate/PE 1:1) to afford compound 35F(pent-4-enyl analogue of 35A, Scheme 6) as an oil (0.41 g, 60%). LCMS(Method A); R_(t): 2.33 min, ([M+H]⁺=378).

To a solution of anhydrous THF (20 ml) containing a mixture of 35F (0.22g, 0.54 mmol) was added 1.35 ml (2.5 eq) of TBAF (1.0 M in THF) underN₂. After the addition, the resulting solution was refluxed for 18hours, cooled and subsequently concentrated in vacuo. Ethyl acetate wasadded and the organic layer was washed with a concentrated NaHCO₃solution, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresulting residue was purified by flash chromatography (ethylacetate/MeOH 1/1) to afford the title compound 33F. (oil, 0.08 g, 53%).LCMS (Method A); R_(t): 1.83 min, ([M+H]⁺=248).

Compound 33F was reacted with 1 equivalent of fumaric acid in EtOH andconcentrated (amorphous). ¹H-NMR (600 MHz, D₆DMSO): δ 7.38 (bs, 1H),6.56 (s, 2H), 6.48-6.44 (m, 1H), 5.88-5.80 (m, 1H), 5.06-4.95 (m, 2H),3.86 (t, J=7 Hz, 2H), 3.60 (bs, 2H), 2.86 (bt, J=7 Hz, 2H), 2.58 (s,3H), 2.42-2.37 (m, 2H), 2.20-2.15 (m, 2H), 1.83-1.77 (m, 2H).

3-(4-Pentyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 33G, Scheme 6)

A mixture of compound 29A/B (1.0 g, 2.49 mmol) (see Scheme 5), CuI (0.05g, 0.249 mmol), Cs₂CO₃ (1.62 g, 4.98 mmol), 1,10-phenanthroline (0.09 g,0.498 mmol) and pentanol (7 ml) was heated at 140° C. for 18 hours(under air).

The mixture was cooled to room temperature. Ethyl acetate was added andthe organic layer was washed met a 5% NaHCO₃ solution, dried (Na₂SO₄),filtered and concentrated in vacuo. The resulting residue was purifiedby flash chromatography (ethyl acetate/PE 1:2) to afford compound 31 Gas an oil (0.24 g, 27%). LCMS (method A); R_(t): 2.76 min, ([M+H]⁺=362).¹H-NMR (400 MHz, mixture of isomers, CDCl₃): δ 9.25 and 8.90 (d, J=2 Hz,1H), 8.61 and 8.52 (dd, J=5 Hz, 2 Hz, 1H), 8.28 and 8.06 (dt, J=8 Hz, 2Hz, 1H), 7.43 and 7.29 (s, 1H), 7.41-7.37 and 7.35-7.31 (m, 1H), 5.39and 5.37 (s, 2H), 4.0-3.92 (m, 2H), 3.71 and 3.60 (bt, J=7 Hz, 2H),1.88-1.80 and 1.76-1.69 (m, 2H), 1.52-1.25 (m, 6H), 0.97-0.90 (m, 3H).

To a solution of anhydrous THF (25 ml) containing 31G (0.23 g, 0.63mmol) were added 1.59 ml (2.5 eq) of TBAF (1.0 M in THF) under N₂. Afterthe addition, the resulting solution was refluxed for 18 hours andsubsequently concentrated in vacuo. Ethyl acetate was added and theorganic layer was washed with a concentrated NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting residue waspurified by flash chromatography (ethyl acetate) to afford3-(4-pentyloxy-1H-pyrazol-3-yl)-pyridine 32G. (oil, 0.14 g, 95%). LCMS(method A); R_(t): 2.27 min, ([M+H]⁺=232). ¹H-NMR (400 MHz, CDCl₃): δ9.25 (d, J=2 Hz, 1H), 8.53 (dd, J=5 Hz, 2 Hz, 1H), 8.23 (dt, J=8 Hz, 2Hz, 1H), 7.36-7.29 (m, 2H), 3.96 (bt, J=7 Hz, 2H), 1.87-1.78 (m, 2H),1.51-1.34 (m, 6H), 0.94 (t, J=7 Hz, 3H).

Compound 32G was converted to the title compound (33G), using themethodology described for the conversion of 21A to 22A (see Scheme 3).

Yield: 85% (amorphous). LCMS (Method A); R_(t): 1.83 min, ([M+H]⁺=250).¹H-NMR (400 MHz, CDCl₃): δ 7.19 (bs, 1H), 6.54-6.50 (bs, 1H), 3.88 (t,J=7 Hz, 2H), 3.40-3.36 (m, 2H), 2.59 (t, J=7 Hz, 2H), 2.45 (s, 3H),2.43-2.37 (m, 2H), 1.81-1.75 (m, 2H), 1.46-1.34 (m, 4H), 0.93 (t, J=7Hz, 3H).

Butyl-[3-(1-Methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-yl]-amine(Compound 42, Scheme 8)

To a solution of concentrated (10 ml) H₂SO₄ containing compound 19(0.725 g, 5 mmol) was added a mixture of 5 ml H₂SO₄ and 5 ml HNO₃dropwise at −10° C. under N₂. After the addition, the resulting solutionwas stirred for 3 hours at room temperature. The mixture was poured intoice followed by subsequent addition of 2 N NaOH. Ethyl acetate was addedand the organic layer was washed with brine, dried (Na₂SO₄), filteredand concentrated in vacuo. The resulting residue was purified by flashchromatography (ethyl acetate) to give compound 38 as an oil (0.57 g,60%). ¹H-NMR (200 MHz, CDCl₃ and D₆DMSO 1/1): δ 8.9 (d, J=2 Hz, 1H), 8.7(d, J=5 Hz, 2 Hz, 1H), 8.05 (dt, J=8 Hz, 2 Hz, 1H), 7.60 (s, 1H),7.48-7.40 (m, 1H).

Compound 38 (0.37 g, 1.9 mmol) was dissolved in MeOH (containingPd(OH)₂/C (0.03 g)). Hydrogenation was accomplished within 3 hours (1atm) at room temperature. The reaction mixture was filtered, washed withethyl acetate/MeOH (1/1) and concentrated in vacuo. The resultingresidue was purified by flash chromatography (ethyl acetate followed byethyl acetate/MeOH 1/1) to afford compound 39 as an oil (0.29 g, 95%).¹H-NMR (200 MHz, CDCl₃ and D₆DMSO 1/1): δ 9.05 (d, J=2 Hz, 1H), 8.51 (d,J=5 Hz, 2 Hz, 1H), 8.09 (dt, J=8 Hz, 2 Hz, 1H), 7.43 (s, 1H), 7.37-7.32(m, 1H).

To a solution of anhydrous CH₃CN (15 ml) containing a mixture ofcompound 39 (0.21 g, 1.3 mmol) and 0.27 ml (1.5 eq) of triethyl aminewas added 0.14 ml of butyryl chloride under N₂. After the addition, theresulting solution was stirred for 3 hours at room temperature andsubsequently concentrated in vacuo. Ethyl acetate was added and theorganic layer was washed with a concentrated NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting residue waspurified by flash chromatography (ethyl acetate) to affordN-(3-pyridin-3-yl-1H-pyrazol)-butyramide 40 (oil, 0.19 g, 77%).(TLCethyl acetate R_(f) 0.16).

Compound 40 was converted to compound 41, using the methodologydescribed for the conversion of 21A to 22A (see Scheme 3).

Yield: 65% (amorphous). LCMS (Method A); R_(t): 0.73 min, ([M+H]⁺=249).¹H-NMR (600 MHz, CDCl₃): δ 8.4 (bs, 1H), 7.5 (bs, 1H), 6.0-5.96 (m, 1H),3.27 (bs, 2H), 2.63 (t, J=7 Hz, 2H), 2.43 (s, 3H), 2.43-2.37 (m, 2H),2.32 (t, J=7 Hz, 2H), 1.76-1.70 (m, 2H), 0.98 (t, J=7 Hz, 3H).

To a solution of anhydrous THF (25 ml) containing compound 41 (0.27 g,1.09 mmol) was added 0.04 g (1.0 eq) LiAlH₄ under N₂. After theaddition, the resulting solution was refluxed for 18 hours and allowedto warm to ambient temperature. To the reaction mixture was added 0.04ml of H₂O, followed by 0.08 ml of 2N NaOH and 0.04 ml of H₂O. Theresulting mixture was warmed for 10 minutes (60° C.), cooled to roomtemperature and filtrated. Ethyl acetate was added and the organic layerwas washed with a concentrated NaHCO₃ solution, dried (Na₂SO₄), filteredand concentrated in vacuo. The resulting residue was purified by flashchromatography (ethyl acetate/MeOH 1/1) to afford the title compound 42.(oil, 0.21 g, 95%). LCMS (method A); R_(t): 1.05 min, ([M+H]⁺=235).¹H-NMR (600 MHz, CDCl₃): δ 7.1 (bs, 1H), 6.17-6.14 (m, 1H), 3.4-3.37 (m,2H), 2.99 (t, J=7 Hz, 2H), 2.64 (t, J=7 Hz, 2H), 2.48 (s, 3H), 2.47-2.42(m, 2H), 1.66-1.60 (m, 2H), 1.47-1.40 (m, 2H), 0.97 (t, J=7 Hz, 3H).

3-(4-Hex-1-ynyl-1H-pyrazol-3-yl)-pyridine (Compound 44A, Scheme 9)

Compound 20B (10.49 g, 38.6 mmol) was converted to3-(1-phenylsulfonyl-4-iodo-1H-pyrazol-3-yl)-pyridine (36B), using themethodology described for the conversion of 20 A to 36A (see Scheme 7).Yield 11.65 g (amorphous, 74%). (TLC diethyl ether R_(f) 0.4) ¹H-NMR(400 MHz, CDCl₃): δ 9.05 (d, J=2 Hz, 1H), 8.65 (dd, J=5 Hz, 2 Hz, 1H),8.27 (s, 1H), 8.12 (dt, J=8 Hz, 2 Hz, 1H), 8.10-8.06 (m, 2H), 7.73-7.67(m, 1H), 7.58 (bt, J=7 Hz, 2H), 7.39-7.34 (m, 1H).

To triethyl amine (10 ml) and DMF (4 ml) containing 36B (0.97 g, 2.36mmol), was added 3 eq of hex-1-yne (0.81 ml). The resulting mixture wasstirred for another 2 hours under N₂. Successively were added 10 mol %of CuI (45 mg), 5 mol % of PdCl₂(PPH₃)₂ (83 mg) and 18 mol % of PPH₃(111 mg). After the addition, the resulting solution was warmed at 70°C. for 18 hours under N₂. After cooling to room temperature, the mixturewas diluted with ethyl acetate, washed three times with a saturatedNaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated. Theresulting residue was purified by flash chromatography (diethyl ether/PE(1/1)) to afford3-(1-phenylsulfonyl-4-hex-1-ynyl-1H-pyrazol-3-yl)-pyridine (43A) as anoil (0.66 g, 77%). ¹H-NMR (400 MHz, CDCl₃): δ 9.5-9.2 (bs, 1H), 8.8-8.4(bs, 1H), 8.34 (bd, J=8 Hz, 1H), 8.21 (s, 1H), 8.08-8.04 (m, 2H), 7.67(bt, J=7 Hz, 1H), 7.57 (bt, J=7 Hz, 2H), 7.41-7.32 (bs, 1H), 2.42 (t,J=7 Hz, 2H), 1.62-1.53 (m, 2H), 1.49-1.39 (m, 2H), 0.93 (t, J=7 Hz, 3H).

Compound 43A (0.66 g, 1.81 mmol), 1.3 g of KOH and 2 ml of NH₂NH₂.H₂Owere combined in diethylene glycol (20 ml) and warmed to reflux for 1hour under N₂. The mixture was cooled, concentrated and redissolved inMeOH. Filtration over 25 g of SCX-2 (MeOH followed by 1 N NH₃/MeOH) andsubsequent purification by flash chromatography (ethyl acetate) affordedthe title compound 44A. Yield 0.37 g (90%). ¹H-NMR (400 MHz, CDCl₃): δ9.25 (d, J=2 Hz, 1H), 8.60 (dd, J=5 Hz, 2 Hz, 1H), 8.34 (dt, J=8 Hz, 2Hz, 1H), 7.73 (s, 1H), 7.39-7.34 (m, 1H), 2.43 ((t, J=7 Hz, 2H),1.64-1.56 (m, 2H), 1.52-1.42 (m, 2H), 0.94 (t, J=7 Hz, 3H).

3-(4-Hex-1-ynyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 45A, Scheme 9)

Compound 44A was converted to compound 45A, using the methodologydescribed for the conversion of 21A to 22A (see Scheme 3). Yield: 90%(amorphous). LCMS (method A); R_(t): 1.79 min, ([M+H]⁺=244). ¹H-NMR (400MHz, CDCl₃): δ 7.57 (s, 1H), 6.78-6.66 (bs, 1H), 3.42-3.38 (m, 2H), 2.59(bt, J=7 Hz, 2H), 2.45 (s, 3H), 2.44-2.37 (m, 2H), 1.62-1.43 (m, 4H),0.94 (t, J=7 Hz, 3H).

3-(4-Hept-1-ynyl-1H-pyrazol-3-yl)-pyridine (Compound 44B)

Compound 44B was prepared following the procedure as described for thesynthesis of compound 44A (see Scheme 9) using hept-1-yne and3-(1-phenylsulfonyl-4-bromo-1H-pyrazol-3-yl)-pyridine (36A). (flashchromatography with diethyl ether) to afford3-(1-phenylsulfonyl-4-hept-1-ynyl-1H-pyrazol-3-yl)-pyridine (43B) as anoil (90%). ¹H-NMR (400 MHz, CDCl₃): δ 9.25 (bs, 1H), 8.6 (bs, 1H), 8.34(bd, J=8 Hz, 1H), 8.21 (s, 1H), 8.06 (bd, J=8 Hz, 2H), 7.67 (bt, J=7 Hz,1H), 7.57 (bt, J=7 Hz, 2H), 7.36-7.30 (m, 1H), 2.42 (t, J=7 Hz, 2H),1.63-1.55 (m, 2H), 1.44-1.28 (m, 4H), 0.89 (t, J=7 Hz, 3H). Compound 43Bwas converted to the title compound 44B, using the methodology describedfor the conversion of 43A to 44A (see Scheme 9). Yield: 98% (oil).¹H-NMR (400 MHz, CDCl₃): δ 9.25 (d, J=2 Hz, 1H), 8.59 (dd, J=5 Hz, 2 Hz,1H), 8.37 (dt, J=8 Hz, 2 Hz, 1H), 7.72 (s, 1H), 7.38-7.33 (m, 1H), 2.42((t, J=7 Hz, 2H), 1.65-1.57 (m, 2H), 1.46-1.30 (m, 4H), 0.90 (t, J=7 Hz,3H).

3-(4-Hept-1-ynyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 45B)

Compound 44B was converted to compound 45B, using the methodologydescribed for the conversion of 21A to 22A (see Scheme 3). Yield: 44%(amorphous). LCMS (method A); R_(t): 1.84 min, ([M+H]⁺=258). ¹H-NMR (400MHz, CDCl₃): δ 7.57 (s, 1H), 6.78-6.66 (bs, 1H), 3.42-3.38 (m, 2H), 2.59(bt, J=7 Hz, 2H), 2.45 (s, 3H), 2.44-2.37 (m, 2H), 1.62-1.43 (m, 4H),0.94 (t, J=7 Hz, 3H).

3-(4-Non-1-ynyl-1H-pyrazol-3-yl)-pyridine (Compound 44C)

Compound 44C was prepared following the procedure as described for thesynthesis of compound 44A (see Scheme 9) using non-1-yne and3-(1-phenylsulfonyl-4-iodo-1H-pyrazol-3-yl)-pyridine (36B). (flashchromatography with diethyl ether/PE 1/1) to afford3-(1-phenylsulfonyl-4-non-1-ynyl-1H-pyrazol-3-yl)-pyridine (43C) as anoil (80%). (TLC diethyl ether R_(f) 0.44).

Compound 43C was converted to the title compound 44C, using themethodology described for the conversion of 43A to 44A (see Scheme 9).Yield: 78% (oil). ¹H-NMR (400 MHz, CDCl₃): δ 9.25 (d, J=2 Hz, 1H), 8.61(dd, J=5 Hz, 2 Hz, 1H), 8.35 (dt, J=8 Hz, 2 Hz, 1H), 7.73 (s, 1H),7.39-7.34 (m, 1H), 2.42 ((t, J=7 Hz, 2H), 1.65-1.56 (m, 2H), 1.47-1.38(m, 2H), 1.37-1.22 (m, 6H), 0.90 (t, J=7 Hz, 3H).

3-(4-Non-1-ynyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 45C)

Compound 44C was converted to compound 45C, using the methodologydescribed for the conversion of 21A to 22A (see Scheme 3). Yield: 79%(amorphous). LCMS (method A); R_(t): 2.17 min, ([M+H]⁺=286). ¹H-NMR (400MHz, CDCl₃): δ 7.57 (s, 1H), 6.74-6.69 (bs, 1H), 3.40-3.36 (m, 2H), 2.58(bt, J=7 Hz, 2H), 2.44 (s, 3H), 2.43-2.36 (m, 2H), 1.63-1.55 (m, 2H),1.48-1.39 (m, 2H), 1.36-1.23 (m, 6H), 0.89 (t, J=7 Hz, 3H).

3-[4-(5-Phenyl-pent-1-ynyl)-1H-pyrazol-3-yl]-pyridine (Compound 44D)

Compound 44C was prepared following the procedure as described for thesynthesis of compound 44A (see Scheme 9) using pent-4-ynyl-benzene and3-(1-phenylsulfonyl-4-iodo-1H-pyrazol-3-yl)-pyridine (36B). (flashchromatography with diethyl ether/PE (1/1)) to afford3-[1-phenylsulfonyl-4-(5-phenyl-pent-1-ynyl)-1H-pyrazol-3-yl]-pyridine(43D) as an oil (80%). ¹H-NMR (400 MHz, CDCl₃): δ 9.3 (d, J=2 Hz, 1H),8.6 (dd, J=5 Hz, 2 Hz, 1H), 8.33 (dt, J=8 Hz, 2 Hz, 1H), 8.22 (s, 1H),8.09-8.05 (m, 2H), 7.68 (bt, J=8 Hz, 1H), 7.57 (bt, J=8 Hz, 2H),7.35-7.25 (m, 3H), 7.21-7.15 (m, 3H), 2.74 ((t, J=7 Hz, 2H), 2.42 ((t,J=7 Hz, 2H), 1.96-1.87 (m, 2H). (TLC diethyl ether R_(f) 0.56).

Compound 43D was converted to the title compound 44D, using themethodology described for the conversion of 43A to 44A (see Scheme 9).Yield: 86% (oil). ¹H-NMR (400 MHz, CDCl₃): δ 9.25 (d, J=2 Hz, 1H), 8.6(dd, J=5 Hz, 2 Hz, 1H), 8.35 (dt, J=8 Hz, 2 Hz, 1H), 7.74 (s, 1H),7.40-7.17 (m, 6H), 2.77 ((t, J=7 Hz, 2H), 2.44 ((t, J=7 Hz, 2H),1.99-1.89 (m, 2H).

3-[4-(5-Phenyl-pent-1-ynyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 45D)

Compound 44D was converted to compound 45D, using the methodologydescribed for the conversion of 21A to 22A (see Scheme 3). Yield: 95%(amorphous). LCMS (method A); R_(t): 1.99 min, ([M+H]⁺=306). ¹H-NMR (400MHz, CDCl₃): δ 7.58 (s, 1H), 7.31-7.18 (m, 5H), 6.79-6.73 (bs, 1H),3.43-3.40 (m, 2H), 2.78 (t, J=7 Hz, 2H), 2.60 (bt, J=7 Hz, 2H),2.45-2.37 (m, 7H), 1.95-1.87 (m, 2H).

3-[4-(5-Cyclohexyl-pent-1-ynyl)-1H-pyrazol-3-yl]-pyridine (Compound 44E)

Compound 44E was prepared following the procedure as described for thesynthesis of compound 44A (see Scheme 9) using pent-4-ynyl-cyclohexaneand 3-(1-phenylsulfonyl-4-iodo-1H-pyrazol-3-yl)-pyridine (36B). (flashchromatography with diethyl ether/PE 1/1) to afford3-[1-phenylsulfonyl-4-(5-cyclohexyl-pent-1-ynyl)-1H-pyrazol-3-yl]-pyridine(43E) as an oil (90%). ¹H-NMR (400 MHz, CDCl₃) δ 9.25 (d, J=2 Hz, 1H),8.6 (dd, J=5 Hz, 2 Hz, 1H), 8.33 (dt, J=8 Hz, 2 Hz, 1H), 8.21 (s, 1H),8.08-8.04 (m, 2H), 7.68 (bt, J=8 Hz, 1H), 7.57 (bt, J=8 Hz, 2H),7.35-7.31 (m, 1H), 2.38 (t, J=7 Hz, 2H), 1.72-1.55 (m, 6H), 1.31-1.10(m, 7H), 0.95-0.8 (m, 2H).

Compound 43E was converted to the title compound 44E, using themethodology described for the conversion of 43A to 44A (see Scheme 9).Yield: 94% (oil). ¹H-NMR (400 MHz, CDCl₃): δ 9.25 (d, J=2 Hz, 1H), 8.6(dd, J=5 Hz, 2 Hz, 1H), 8.35 (dt, J=8 Hz, 2 Hz, 1H), 7.72 (s, 1H),7.39-7.34 (m, 1H), 2.40 (t, J=7 Hz, 2H), 1.73-1.57 (m, 6H), 1.35-1.10(m, 7H), 0.93-0.75 (m, 2H).

3-[4-(5-Cyclohexyl-pent-1-ynyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine(Compound 45E)

Compound 44E was converted to compound 45E, using the methodologydescribed for the conversion of 21A to 22A (see Scheme 3). Yield: 90%(amorphous). LCMS (method A); R_(t) 2.28 min, ([M+H]⁺=312). ¹H-NMR (400MHz, CDCl₃): δ 7.57 (s, 1H), 6.76-6.71 (bs, 1H), 3.41-3.37 (m, 2H), 2.59(bt, J=7 Hz, 2H), 2.45-2.35 (m, 7H), 1.75-1.55 (m, 6H), 1.35-1.10 (m,7H), 0.94-0.8 (m, 2H).

3-(4-Hex-1-enyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 47A, Scheme 9)

To toluene (20 ml) containing 36A (0.67 g, 1.84 mmol) (see Scheme 7),was added 1.5 eq of (E)-hexene-1-ylboronic acid (0.35 g). The resultingmixture was stirred for 2 hours under N₂. Successively were added 2 eqof K₃PO₄ (0.78 g), 4 mol % of Pd(OAc)₂ (16.5 mg) and 8 mol % of S-Phos(60.4 mg). After the addition, the resulting solution was warmed at 90°C. for 18 hours under N₂. After cooling to room temperature, the mixturewas diluted with ethyl acetate, washed three times with a saturatedNaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated. Theresulting residue was purified by flash chromatography (diethyl ether/PE1/1) to afford3-(1-phenylsulfonyl-4-hex-1-enyl-1H-pyrazol-3-yl)-pyridine (46A) as anoil (0.38 g, 61%). ¹H-NMR (400 MHz, CDCl₃): δ 8.8 (d, J=2 Hz, 1H), 8.6(dd, J=5 Hz, 2 Hz, 1H), 8.15 (s, 1H), 8.10-8.05 (m, 2H), 7.94 (dt, J=8Hz, 2 Hz, 1H), 7.70-7.64 (m, 1H), 7.56 (bt, J=8 Hz, 2H), 7.37-7.33 (m,1H), 6.19-6.02 (m, 1H), 2.2-2.13 (m, 2H), 1.45-1.29 (m, 4H), 0.90 (t,J=7 Hz, 3H).

Compound 46A (0.34 g, 0.97 mmol), 0.7 g of KOH and 1 ml of NH₂NH₂.H₂Owere combined in diethylene glycol (10 ml) and warmed to reflux for 1hour under N₂. The mixture was cooled, concentrated and redissolved inMeOH. Filtration over 25 g of SCX-2 (MeOH followed by 1 N NH₃/MeOH) andsubsequent purification by flash chromatography (ethyl acetate) afforded3-(4-hex-1-enyl-1H-pyrazol-3-yl)-pyridine (the deprotected analog of46A). Yield 0.18 g (86%). (TLC diethyl ether R_(f) 0.18).3-(4-Hex-1-enyl-1H-pyrazol-3-yl)-pyridine was converted to the titlecompound 47A, using the methodology described for the conversion of 21 Ato 22A (see Scheme 3). Yield: 50% (amorphous). LCMS (method A); R_(t):2.30 min, ([M+H]⁺=246). ¹H-NMR (400 MHz, CDCl₃): δ 7.59 (s, 1H), 6.22(bd, J=16 Hz, 1H), 6.03-5.98 (bs, 1H), 5.98-5.88 (m, 1H), 3.26-3.21 (m,2H), 2.63 (bt, J=7 Hz, 2H), 2.44 (s, 3H), 2.43-2.36 (m, 2H), 2.19-2.11(m, 2H), 1.46-1.29 (m, 4H), 0.91 (t, J=7 Hz, 3H).

3-{4-2-[-(3-Fluor-phenyl)-vinyl]-1H-pyrazol-3-yl}-1,2,5,6-tetrahydro-1-methylpyridine(Compound 47B)

To toluene (20 ml) containing 36A (0.48 g, 1.32 mmol) (see Scheme 7),was added 1.5 eq of (E)-2-(3-fluorphenyl)-vinyl boronic acid (0.33 g).The resulting mixture was stirred for 2 hours under N₂. Successivelywere added 2 eq of K₃PO₄ (0.56 g), 4 mol % of Pd(OAc)₂ (8.8 mg) and 8mol % of S-Phos (32 mg). After the addition, the resulting solution waswarmed at 90° C. for 18 hours under N₂. After cooling to roomtemperature, the mixture was diluted with ethyl acetate, washed threetimes with a saturated NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated. The resulting residue was purified by flash chromatography(diethyl ether/PE 1/1) to afford3-(1-phenylsulfonyl-4-[2-(3-fluoro-phenyl)-vinyl]-1H-pyrazol-3-yl)-pyridine(46B) as an oil (0.39 g, 73%). ¹H-NMR (400 MHz, CDCl₃): δ 8.85 (d, J=2Hz, 1H), 8.65 (dd, J=5 Hz, 2 Hz, 1H), 8.36 (s, 1H), 8.13-8.08 (m, 2H),7.95 (dt, J=8 Hz, 2 Hz, 1H), 7.72-7.67 (m, 1H), 7.58 (bt, J=8 Hz, 2H),7.41-7.37 (m, 1H), 7.33-7.27 (m, 1H), 7.16 (bd, J=7 Hz, 1H), 7.12-7.07(m, 1H), 7.0-6.94 (m, 1H), 6.92 (d, J=16 Hz, 1H), 6.82 (d, J=16 Hz, 1H).

Compound 46B (1.06 g, 2.62 mmol), 1.3 g of KOH and 2 ml NH₂NH₂.H₂O werecombined in diethylene glycol (25 ml) and warmed to reflux for 1 hourunder N₂. The mixture was cooled, concentrated and redissolved in MeOH.Filtration over 25 g of SCX-2 (MeOH followed by 1 N NH₃/MeOH) andsubsequent purification by flash chromatography (ethyl acetate) afforded3-{4-[2-(3-fluor-phenyl)-vinyl]-1H-pyrazol-3-yl}-pyridine (thedeprotected analog of 46B). Yield 0.42 g (60.4%). ¹H-NMR (400 MHz,CDCl₃): δ 8.85 (d, J=2 Hz, 1H), 8.65 (dd, J=5 Hz, 2 Hz, 1H), 7.95-7.90(m, 2H), 7.45-7.41 (m, 1H), 7.32-7.27 (m, 1H), 7.20-7.16 (m, 1H),7.14-7.09 (m, 1H), 6.99 (d, J=16 Hz, 1H), 6.96-6.86 (m, 2H).

3-{4-[2-(3-Fluor-phenyl)-vinyl]-1H-pyrazol-3-yl}-pyridine was convertedto the title compound 47B, using the methodology described for theconversion of 21A to 22A (see Scheme 3). Yield: 67% (amorphous). LCMS(method A); R_(t): 1.79 min, ([M+H]⁺=284). ¹H-NMR (400 MHz, CDCl₃): δ7.78 (s, 1H), 7.31-7.25 (m, 1H), 7.20-7.10 (m, 2H), 7.0-6.88 (m, 2H),6.81 (d, J=16 Hz, 1H), 6.07-6.01 (m, 1H), 3.33-3.25 (m, 2H), 2.69 (bt,J=7 Hz, 2H), 2.50-2.42 (m, 5H).

3-(4 Oct-1-enyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 47C)

To toluene (20 ml) containing 36A (0.91 g, 2.5 mmol) (see Scheme 7), wasadded 1.5 eq (E)-octene-1-ylboronic acid (0.59 g). The resulting mixturewas stirred for 2 hours under N₂. Successively were added 2 eq of K₃PO₄(1.06 g), 4 mol % of Pd(OAc)₂ (22.4 mg) and 8 mol % of S-Phos (82 mg).After the addition, the resulting solution was warmed at 90° C. for 18hours under N₂. After cooling to room temperature, the mixture wasdiluted with ethyl acetate, washed three times with a saturated NaHCO₃solution, dried (Na₂SO₄), filtered and concentrated. The resultingresidue was purified by flash chromatography (diethyl ether/PE 1/1) toafford 3-(1-phenylsulfonyl-4-oct-1-enyl-1H-pyrazol-3-yl)-pyridine (46C)as an oil (0.31 g, 32%). ¹H-NMR (400 MHz, CDCl₃): δ 8.85 (d, J=2 Hz,1H), 8.65 (dd, J=5 Hz, 2 Hz, 1H), 8.15 (s, 1H), 8.08-8.05 (m, 2H), 7.93(dt, J=8 Hz, 2 Hz, 1H), 7.69-7.64 (m, 1H), 7.59-7.52 (m, 2H), 7.37-7.33(m, 1H), 6.19 (d, J=16 Hz, 1H), 6.10-6.03 (m, 1H), 2.19-2.12 (m, 2H),1.45-1.37 (m, 2H), 1.36-1.23 (m, 6H), 0.90 (t, J=7 Hz, 3H).

Compound 46C (0.35 g, 0.89 mmol), 0.7 g of KOH and 1 ml of NH₂NH₂.H₂Owere combined in diethylene glycol (10 ml) and warmed to reflux for 1hour under N₂. The mixture was cooled, concentrated and re-dissolved inMeOH. Filtration over 25 g of SCX-2 (MeOH followed by 1 N NH₃/MeOH) andsubsequent purification by flash chromatography (ethyl acetate) afforded3-(4-oct-1-enyl-1H-pyrazol-3-yl)-pyridine (the deprotected analog of46C). Yield 0.19 g (95%). ¹H-NMR (400 MHz, CDCl₃): δ 8.85 (d, J=2 Hz,1H), 8.65 (dd, J=5 Hz, 2 Hz, 1H), 7.91 (dt, J=8 Hz, 2 Hz, 1H), 7.71 (s,1H), 7.41-7.36 (m, 1H), 6.27 (d, J=16 Hz, 1H), 6.07-5.98 (m, 1H),2.19-2.12 (m, 2H), 1.46-1.38 (m, 2H), 1.37-1.23 (m, 6H), 0.89 (t, J=7Hz, 3H).

3-(4 Oct-1-enyl-1H-pyrazol-3-yl)-pyridine was converted to the titlecompound 47C, using the methodology described for the conversion of 21 Ato 22A (see Scheme 3). Yield: 95% (amorphous). ¹H-NMR (400 MHz, CDCl₃):δ 7.58 (s, 1H), 6.24 (bd, J=16 Hz, 1H), 6.07-6.02 (m, 1H), 5.98-5.89 (m,1H), 3.29-3.25 (m, 2H), 2.63 (bt, J=7 Hz, 2H), 2.46 (s, 3H), 2.44-2.38(m, 2H), 2.18-2.12 (m, 2H), 1.46-1.38 (m, 2H), 1.38-1.24 (m, 6H), 0.91(t, J=7 Hz, 3H).

3-(4-Butylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane (Compound49A, Scheme 10)

To a solution of anhydrous THF (150 ml) containing compound 48 (0.5 g,1.65 mmol), prepared according to Biorganic & Medicinal Chemistry, 8,2000, 449-454, were added 2.1 eq of n-BuLi (1.39 ml, 2.5 M in hexane)dropwise at −78° C. under N₂. After the addition, the resulting solutionwas stirred for 1.5 hours at −78° C. At this temperature 1.1 eq ofethyldisulfanylethane (0.35 ml) were added and the resulting solutionwas stirred for 1 hour at −78° C. and subsequently allowed to warm toambient temperature overnight. Then the mixture was quenched with asaturated NH₄Cl solution at 0° C. and concentrated in vacuo. Ethylacetate was added and the organic layer was washed with 2 N NaOH, dried(Na₂SO₄), filtered and concentrated in vacuo. Purification by flashchromatography (MeOH) afforded the title compound 49A (amorphous, 0.15g, 35%). Compound 49A was reacted with 1 equivalent of fumaric acid inEtOH and concentrated. (solid). mp 162-164° C. LCMS (method A); R_(t):1.62 min, ([M+H]⁺=266). ¹H-NMR (400 MHz, D₆DMSO): δ 7.83 (s, 1H), 6.43(s, 2H), 3.60-3.39 (m, 3H), 3.25-3.00 (m, 4H), 2.58 (bt, J=7 Hz, 2H),2.10-2.05 (m, 1H), 1.98-1.83 (m, 2H), 1.78-1.68 (m, 1H), 1.48-1.30 (m,4H), 0.84 (t, J=7 Hz, 3H).

3-(4-Pentylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane (Compound49B, Scheme 10)

Compound 48 (2.50 g; 8.25 mmol), K₂CO₃ (1.82 g; 13.2 mmol) andpentane-1-thiol (1.53 ml, 12.4 mmol) were dissolved in 30 ml of DMF andthe solution was degassed for 45 minutes with argon. To this solutionwere added Pd₂(dba)₃ (755 mg; 0.83 mmol) and Xantphos (953 mg; 1.65mmol). After the addition, the reaction mixture was heated up to 120° C.and stirred for 20 hours under N₂. The mixture was cooled, concentratedand re-dissolved in MeOH. Filtration over 25 g of SCX-2 (MeOH followedby 1 N NH₃/MeOH) and subsequent purification by flash chromatography(EtOH) afforded the title compound 49B as an oil. Yield 395 mg (17%).Compound 49B was reacted with 1 equivalent of fumaric acid in EtOH andconcentrated (solid). mp 142-145° C. ¹H-NMR (600 MHz, D₆DMSO): δ 7.83(s, 1H), 6.48 (s, 2H), 3.58-3.51 (m, 1H), 3.48-3.41 (m, 2H), 3.25-3.15(m, 3H), 3.11-3.03 (m, 1H), 2.61-2.53 (m, 2H), 2.11-2.06 (m, 1H),1.97-1.85 (m, 2H), 1.77-1.69 (m, 1H), 1.59-1.52 (m, 1H), 1.48-1.41 (m,2H), 1.34-1.22 (m, 4H), 0.83 (t, J=7 Hz, 3H).

3-(4-Methylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane (Compound49C)

Compound 48 (2.50 g; 8.25 mmol)(see Scheme 10) was dissolved in 30 ml ofDMF and the solution was degassed for 45 minutes with argon. To thissolution were added NaSMe (867 mg, 12.4 mmol), Pd₂(dba)₃ (755 mg; 0.83mmol) and Xantphos (953 mg; 1.65 mmol). After the addition, the reactionmixture was heated to 120° C. and stirred for 20 hours under N₂. Themixture was cooled, concentrated and re-dissolved in MeOH. Filtrationover 25 g of SCX-2 (MeOH followed by 1 N NH₃/MeOH) and subsequentpurification by flash chromatography (EtOH) afforded compound 49C (oil).Crystallization from diethyl ether gave the title compound (solid).mp145-147° C. Yield: 290 mg (16%). ¹H-NMR (600 MHz, D₆DMSO): δ7.70 (s,1H), 3.21-3.12 (m, 1H), 3.10-3.01 (m, 2H), 2.92-2.85 (m, 1H), 2.81-2.73(m, 2H), 2.68-2.61 (m, 1H), 2.21 (s, 3H), 1.81-1.78 (m, 1H), 1.68-1.55(m, 3H), 1.25-1.18 (m, 1H).

3-(4-Ethylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane (Compound49D)

Compound 49D was prepared following the procedure as described for thesynthesis of compound 49B (see Scheme 10) using ethanethiol as reagent.Subsequent purification by flash chromatography (EtOH toEtOH/triethylamine 99/1) afforded compound 49D.

Yield: 30% (oil). ¹H-NMR (600 MHz, D₆DMSO): δ 7.69 (s, 1H), 3.16-2.99(m, 3H), 2.92-2.84 (m, 1H), 2.80-2.71 (m, 2H), 2.67-2.60 (m, 1H),2.56-2.51 (m, 2H), 1.78-1.75 (m, 1H), 1.66-1.54 (m, 3H), 1.25-1.18 (m,1H), 1.08 (t, J=7 Hz, 3H).

3-(4-Propylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane (Compound49E)

Compound 49E was prepared following the procedure as described for thesynthesis of compound 49B (see Scheme 10) using propane-1-thiol asreagent. Subsequent purification by flash chromatography (EtOH toEtOH/triethylamine 99/1) afforded compound 49E.

Yield: 25% (amorphous). ¹H-NMR (600 MHz, D₆DMSO): δ 7.72-7.64 (bs, 1H),3.16-2.99 (m, 3H), 2.93-2.84 (m, 1H), 2.80-2.71 (m, 2H), 2.67-2.60 (m,1H), 2.54-2.48 (m, 2H+DMSO), 1.78-1.75 (m, 1H), 1.66-1.54 (m, 3H),1.47-1.40 (m, 2H), 1.25-1.18 (m, 1H), 0.90 (t, J=7 Hz, 3H).

3-(4-Hexylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane (Compound49F)

Compound 49F was prepared following the procedure as described for thesynthesis of compound 49B (see Scheme 10) using hexane-1-thiol asreagent. Subsequent purification by flash chromatography (EtOH) affordedcompound 49F.

Yield: 25% (oil). Compound 49F was reacted with 1 equivalent of fumaricacid in EtOH and concentrated (solid). mp 130° C. ¹H-NMR (600 MHz,D₆DMSO): δ 7.81 (s, 1H), 6.46 (s, 2H), 3.55-3.49 (m, 1H), 3.45-3.39 (m,2H), 3.22-3.13 (m, 3H), 3.08-3.02 (m, 1H), 2.60-2.52 (m, 2H), 2.09-2.05(m, 1H), 1.95-1.83 (m, 2H), 1.75-1.68 (m, 1H), 1.57-1.51 (m, 1H),1.46-1.40 (m, 2H), 1.35-1.29 (m, 2H), 1.27-1.17 (m, 4H), 0.83 (t, J=7Hz, 3H).

3-(4-Phenethylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane(Compound 49G)

Compound 49G was prepared following the procedure as described for thesynthesis of compound 49B (see Scheme 10) using 3-phenyl-1-propanethiolas reagent. Subsequent purification by flash chromatography (EtOH)afforded compound 49G.

Yield: 11% (oil). Compound 49G was reacted with 1 equivalent of fumaricacid in EtOH and concentrated (amorphous). ¹H-NMR (600 MHz, D₆DMSO): δ7.86 (s, 1H), 7.26 (t, J=8 Hz, 2H), 7.19-7.14 (m, 3H), 6.49 (s, 2H),3.56-3.50 (m, 1H), 3.46-3.39 (m, 2H), 3.24-3.14 (m, 3H), 3.10-3.03 (m,1H), 2.66 (t, J=7 Hz, 2H), 2.60-2.53 (m, 2H), 2.03-2.00 (bs, 1H),1.94-1.82 (m, 2H), 1.77-1.68 (m, 3H), 1.56-1.50 (m, 1H).

3-[4-(3-Methyl-butylsulfanyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane(Compound 49H)

Compound 49H was prepared following the procedure as described for thesynthesis of compound 49B (see Scheme 10) using 3-methyl-1-butanethiolas reagent. Subsequent purification by flash chromatography (EtOH)afforded compound 49G.

Yield: 20% (oil). Compound 49G was reacted with 1 equivalent of fumaricacid in EtOH and concentrated (solid). mp 157-159° C. ¹H-NMR (600 MHz,D₆DMSO): δ 7.83 (s, 1H), 6.47 (s, 2H), 3.56-3.50 (m, 1H), 3.46-3.40 (m,2H), 3.24-3.15 (m, 3H), 3.09-3.03 (m, 1H), 2.58 (t, J=7 Hz, 2H),2.09-2.06 (bs, 1H), 1.96-1.84 (m, 2H), 1.76-1.68 (m, 1H), 1.67-1.59 (m,1H), 1.58-1.52 (m, 1H), 1.38-1.30 (m, 2H), 0.83 (d, J=7 Hz, 6H).

3-[4-(4,4-Difluoro-but-3-enylsulfanyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane(Compound 49I)

Compound 49I was prepared following the procedure as described for thesynthesis of compound 21A (see Scheme 3) using3-phenyl-propyldisulfanyl-3-propylbenzene as the disulfide (preparedaccording to the methodology described in Tetrahedron Letters, 42, 2001,6741-6743) and 3-(4-iodo-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane(compound 48, see Scheme 10). Purification conditions were: PrepHPLC(system CHSLCPO₂), Column: Inertsil ODS-3, 8 um. Eluens 10%/90%CH₃CN/H₂O+HCOOH, 50 ml/min. LCMS (method A): R_(t): 1.16 min,([M+H]⁺=300). Yield: 4.5%. (oil). ¹H-NMR (600 MHz, CDCl₃): δ 7.63 (s,1H), 4.24 and 4.17 (ddt, J=7 Hz, 26 Hz, 3 Hz, 1H), 3.91-3.84 (m, 1H),3.51-3.37 (m, 3H), 3.32-3.19 (m, 2H), 3.12-3.03 (m, 1H), 2.57 (t, J=7Hz, 2H), 2.23-2.15 (m, 3H), 2.12-2.01 (m, 1H), 2.01-1.89 (m, 2H),1.61-1.51 (m, 1H).

3-(4-Butoxy-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane (Compound 52A,Scheme 10)

A 60% dispersion of NaH in mineral oil (1.5 g, 38 mmol) was added to asolution of anhydrous THF (300 ml) containing3-(4-iodo-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane (compound 48, 9.6g, 31.7 mmol) under N₂. The resulting mixture was stirred for 2 hours atroom temperature until all solids had dissolved. The reaction mixturewas subsequently treated with 38.4 mmol (6.74 ml) of2-chloromethoxy-ethyl-trimethylsilane (SEM-Cl). The resulting mixturewas stirred for 20 hours at room temperature. Because of partialquaternization of the desired product (50), TBAF (1 M solution in THF,45 ml, 45 mmol) was added and the mixture was stirred for 20 hours atroom temperature. Ethyl acetate was added to the mixture and the organiclayer was washed with a 2 N NaOH solution followed by brine, dried(Na₂SO₄), filtered and concentrated to afford3-[4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane(50). Yield: 11.6 g, 26.7 mmol, 84%. LCMS (method B); R_(t): 3.11 min,([M+H]⁺=434).

A mixture of compound 50 (2.5 g, 5.77 mmol), CuI (1.37 g, 7.19 mmol),Cs₂CO₃ (3.90 g, 12 mmol), 1,10-phenanthroline (2.60 g, 14.4 mmol) andbutanol (25 ml) was heated at 150° C. for 4 hours in the microwave.

The mixture was cooled to room temperature. Ethyl acetate was added andthe organic layer was washed met a 2 N NaOH solution, dried (Na₂SO₄),filtered and concentrated in vacuo. The resulting residue was purifiedby flash chromatography (gradient EtOH to EtOH/triethylamine 300/1)followed by a second flash chromatography (EtOH/ethylacetate/triethylamine 25/75/1) to afford compound 51A as an oil (0.33 g,15%). LCMS (method B); R_(t): 3.27 min, ([M+H]⁺=380).

To a solution of anhydrous THF (5 ml) containing compound 51A (0.33 g,0.86 mmol) were added 3.5 ml of TBAF (1.0 M in THF) under N₂. After theaddition, the resulting solution was stirred for 20 hours at roomtemperature and subsequently concentrated in vacuo. Ethyl acetate wasadded and the organic layer was washed with a concentrated NaHCO₃solution, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresulting residue was purified by flash chromatography (gradient EtOH toEtOH/triethylamine 97/3), followed by a preparative HPLC purification:PrepHPLC (system CHSLCPO₂), Column: Inertsil ODS-3, 8 um. Eluens 10%/90%CH₃CN/H₂O+HCOOH, 50 ml/min, to afford the title compound 52A. (oil, 0.1g, 45%). LCMS (method A): R_(t): 1.0 min, ([M+H]⁺=250). ¹H-NMR (600 MHz,D₆DMSO+a few drops of HCOOH): δ 8.63 (s, 1H), 7.2 (s, 1H), 3.99-3.93 (m,1H), 3.85 (t, J=7 Hz, 2H), 3.54-3.26 (m, 5H), 3.19-3.12 (m, 1H),2.36-2.32 (m, 1H), 2.12-1.95 (m, 3H), 1.76-1.70 (m, 2H), 1.67-1.60 (m,1H), 1.50-1.42 (m, 2H), 0.98 (t, J=7 Hz, 3H).

3-(4-Propoxy-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane (Compound 52B)

Compound 52B was prepared following the procedure as described for thesynthesis of compound 52A (see Scheme 10) using propanol and3-[4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane(50). Work-up and flash chromatography (gradient EtOH toEtOH/triethylamine 300/1) followed by a second flash chromatography(EtOH/ethyl acetate/triethylamine 25/75/1) afforded compound 51B as anoil (14%). LCMS (method B): R_(t): 7.15 min, ([M+H]⁺=366). Compound 51Awas subsequently deprotected (TBAF/THF) and purified by flashchromatography (gradient EtOH to EtOH/triethylamine 97/3), followed by apreparative TLC purification (CH₃CN/H₂O) to afford the title compound52B as an oil. (51%). LCMS (method A); R_(t): 0.91 min, ([M+H]⁺=236).¹H-NMR (600 MHz, D₆DMSO): δ 7.34 (s, 1H), 3.74 (t, J=7 Hz, 2H),3.24-3.19 (m, 1H), 3.03-2.96 (m, 1H), 2.92-2.87 (m, 1H), 2.86-2.74 (m,3H), 2.69-2.62 (m, 1H), 1.88-1.84 (m, 1H), 1.67-1.55 (m, 5H), 1.26-1.20(m, 1H), 0.92 (t, J=7 Hz, 3H).

3-(4-Pentyloxy-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane (Compound 52C)

Compound 52C was prepared following the procedure as described for thesynthesis of compound 52A (see Scheme 10) using pentanol (25 ml) and3-[4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane(50), (2 g, 4.61 mmol). Work-up and flash chromatography (gradient EtOHto EtOH/triethylamine 300/1) followed by a second flash chromatography(EtOH/ethyl acetate/triethylamine 25/75/1) afforded compound 51C as anoil (0.46 g, 15%). LCMS (method B); R_(t): 3.30 min, ([M+H]⁺=394).

To a solution of SEM-protected pyrazole 51C (0.46 g, 1.2 mmol) in EtOH(5 ml) was added HCl (4 M in dioxane, 1 ml, 4 mmol) and the reactionmixture was stirred at 75° C. for 20 hours. Subsequent purification byflash chromatography (gradient EtOH to EtOH/triethylamine 97/3),followed by a preparative HPLC purification: PrepHPLC (system CHSLCPO₂),Column: Inertsil ODS-3, 8 um. Eluens 10%/90% CH₃CN/H₂O+HCOOH, 50 ml/min,afforded the title compound 52C. (oil, 60 mg, 19%).

¹H-NMR (600 MHz, D₆DMSO+a few drops of HCOOH): δ 8.65 (s, ˜1H), 7.2 (s,1H), 3.96-3.90 (m, 1H), 3.84 (t, J=7 Hz, 2H), 3.54-3.46 (m, 1H),3.45-3.26 (m, 4H), 3.19-3.12 (m, 1H), 2.36-2.32 (m, 1H), 2.12-1.95 (m,3H), 1.79-1.74 (m, 2H), 1.67-1.60 (m, 1H), 1.45-1.35 (m, 4H), 0.95 (t,J=7 Hz, 3H).

Exo-6-(1H-pyrazol-3-yl)-1-azabicyclo[3.2.1]octan-6-ol (Compound 55,Scheme 11)

A suspension of propargylaldehyde diethyl acetale (14.62 g, 114 mmol)and t-BuOK (14.92 g, 133 mmol) in 350 ml of anhydrous THF was stirredfor 1 hour at −10° C. under N₂. Then a suspension of1-aza-bicyclo[3.2.1]octan-6-one (53, J. Med. Chem., 36, 1993, 683-689)(11.92 g, 95 mmol) in 100 ml of THF was added and the resultinghomogeneous reaction mixture was stirred for another 2 hours at 0° C.Then the mixture was quenched with an aqueous acetic acid solution at 0°C. and concentrated in vacuo. Ethyl acetate was added and the organiclayer was washed with 2 N NaOH, dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification by flash chromatography(dichloromethane/MeOH/NH₄OH 93/7/0.5) afforded6-(3,3-diethoxy-prop-1-ynyl)-1-azabicyclo[3.2.1]octan-6-ol (54) as anoil (20.87 g, 86%). LCMS (Method A): R_(t): 1.18 min, ([M+H]⁺=254).¹H-NMR (400 MHz, CDCl₃): δ 5.28 (s, 1H), 3.74-3.65 (m, 2H), 3.61-3.52(m, 2H), 3.45 (d, J=13 Hz, 1H), 3.12-3.04 (m, 1H), 3.0-2.82 (m, 4H),2.22-2.18 (m, 1H), 2.17-2.02 (m, 1H), 1.98-1.89 (m, 1H), 1.71-1.61 (m,1H), 1.39-1.30 (m, 1H), 1.22 (t, J=7 Hz, 6H).

Compound 54 (15.39 g, 60.7 mmol) and 7.02 g of hydrazine dihydrochloridewere combined in EtOH/H₂O (3/2, 250 ml) and warmed to reflux for 18 hourunder N₂. The mixture was cooled, concentrated and re-dissolved in MeOH.To the reaction mixture was added Amberlyte IRA-95 (basic) andsubsequently stirred for 18 hours at room temperature. The mixture wasfiltrated, concentrated and re-dissolved in MeOH. Filtration over 100 gof SCX-2 (MeOH followed by 1 N NH₃/MeOH) afforded the title compound 55(amorphous). Yield 8.45 g (72%). ¹H-NMR (600 MHz, D₆DMSO+a few drops ofCF₃COOH): δ 7.70 (d, J=2 Hz, 1H), 6.42 (d, J=2 Hz, 1H), 4.24-4.20 (m,1H), 3.41-3.31 (m, 4H), 3.25-3.21 (m, 1H), 2.45-2.42 (m, 1H), 2.40-2.30(m, 1H), 2.10-2.04 (m, 1H), 1.74-1.64 (m, 2H), used techniques are DEPT,HSQC, COSY, HMBC, ROESY and NOESY

Endo-6-(1H-pyrazol-3-yl)-1-azabicyclo[3.2.1]octane (Compound 58, Scheme11)

Compound 55 (7.83 g, 41 mmol) and 9.81 ml (120 mmol) of pyridine werecombined in benzene (150 ml). Acetic anhydride was added (11.48 ml, 120mmol) and the reaction mixture was warmed to 40° C. for 72 hour underN₂. The mixture was cooled, concentrated and re-dissolved in MeOH.Filtration over 100 g of SCX-2 (MeOH followed by 1 N NH₃/MeOH) affordedcompound 56 (amorphous, 9.6 g, ˜100%), LCMS (method A): R_(t): 0.98 min,([M+H]⁺=236), which was used without further purification.

Compound 56 (1.2 g, 5.1 mmol) was heated (in the neat) at 200° C. for 5min under reduced pressure (23 mbar) and subsequently cooled to roomtemperature. Purification by flash chromatography(dichloromethane/MeOH/NH₄OH 85/15/1) afforded6-(1H-pyrazol-3-yl)-1-azabicyclo[3.2.1]oct-6-ene (57) as an oil (0.49 g,49%). LCMS (Method A); R_(t): 1.27 min, ([M+H]⁺=176). ¹H-NMR (400 MHz,CDCl₃): δ 7.56 (d, J=2 Hz, 1H), 6.43 (s, 1H), 6.36 (d, J=2 Hz, 1H),3.50-3.45 (m, 1H), 3.06-2.97 (m, 1H), 2.93 (d, J=10 Hz, 1H), 2.86-2.79(m, 2H), 2.06-1.93 (m, 1H), 1.78-1.72 (m, 1H), 1.49-1.41 (m, 1H).

Compound 57 (3.84 g, 21.9 mmol), 6.9 g of ammonium formate (110 mmol)and 20% Pd(OH)₂/C (340 mg) were combined in MeOH (150 ml) and warmed toreflux for 1 hour. The mixture was cooled, filtered, concentrated andre-dissolved in MeOH. Filtration over 40 g of SCX-2 (MeOH followed by 1N NH₃/MeOH) and subsequent purification by flash chromatography(MeOH/triethylamine 90/3) affordedendo-6-(1H-pyrazol-3-yl)-1-azabicyclo[3.2.1]octane (58), (amorphous, 2.8g, 73%). LCMS (method A); R_(t): 0.80 min, ([M+H]⁺=178). ¹H-NMR (600MHz, D₆DMSO/CDCl₃ (1/1)): δ 7.54 (d, J=2 Hz, 1H), 6.16 (d, J=2 Hz, 1H),3.98-3.92 (m, 1H), 3.90-3.84 (m, 1H), 3.82-3.77 (m, 1H), 3.53-3.48 (m,1H), 3.32-3.24 (m, 3H), 2.82-2.77 (m, 1H), 2.03-1.94 (m, 1H), 1.68-1.60(m, 1H), 1.58-1.52 (m, 1H), 1.51-1.47 (m, 1H), used techniques are DEPT,HSQC, COSY, HMBC, ROESY and NOESY.

Endo-6-(4-pentylsulfanyl-1H-Pyrazol-3-yl)-1-azabicyclo[3.2.1]octane(Compound 60A, Scheme 11)

To a solution of 58 (1.49 g, 8.41 mmol) in anhydrous DMF (60 ml) at −10°C. were added 2.68 g (10.93 mmol) of N-iodosuccinimide. The reactionmixture was stirred for 2 hours at −10° C. and 1 hour at roomtemperature. The solvent was (partly) removed under reduced pressure.MeOH was added and the resulting reaction mixture was filtrated over 120g of SCX-2 (MeOH followed by 1 N NH₃/MeOH) to affordendo-6-(4-iodo-1H-pyrazol-3-yl)-1-azabicyclo[3.2.1]octane (59),(amorphous, 1.73 g, 67%). LCMS (Method A); R_(t): 1.25 min,([M+H]⁺=304). ¹H-NMR (600 MHz, D₆DMSO+CF₃COOH): δ 7.72 (s, 1H),4.08-4.03 (m, 1H), 3.80-3.75 (m, 1H), 3.73-3.68 (m, 1H), 3.50-3.45 (m,1H), 3.34-3.25 (m, 3H), 3.04-3.0 (m, 1H), 2.24-2.14 (m, 1H), 1.64-1.57(m, 1H), 1.50-1.42 (m, 1H), 1.22-1.17 (m, 1H), used techniques are DEPT,HSQC, COSY, HMBC, ROESY and NOESY.

Compound 59 (0.50 g; 1.65 mmol), K₂CO₃ (0.3 g; 2.14 mmol) andpentane-1-thiol (0.26 ml, 2.06 mmol) were dissolved in 20 ml ofxylene/DMF (9/1) and the solution was degassed for 45 minutes withargon. To this solution were added Pd₂(dba)₃ (150 mg; 0.165 mmol) andXantphos (190 mg; 0.33 mmol). After the addition, the reaction mixturewas heated up to 130° C. and stirred for 20 hours under N₂. The mixturewas cooled, concentrated and re-dissolved in MeOH. Filtration over 75 gof SCX-2 (MeOH followed by 1 N NH₃/MeOH) and subsequent purification byflash chromatography (MeOH/triethylamine (97/3)) afforded the titlecompound 60A as an oil. Yield 150 mg (32%). Compound 60A was reactedwith 1 equivalent of fumaric acid in EtOH and concentrated (amorphous).

LCMS (method A); R_(t): 1.39 min, ([M+H]⁺=280). ¹H-NMR (600 MHz,D₆DMSO): δ 7.85 (s, 1H), 6.43 (s, 2H), 3.80-3.70 (m, 2H), 3.63-3.58 (m,1H), 3.28-3.22 (m, 1H), 3.20-3.19 (m, 3H), 2.82-2.78 (m, 1H), 2.63-2.55(m, 2H), 2.12-2.01 (m, 1H), 1.65-1.56 (m, 1H), 1.50-1.44 (m, 2H),1.37-1.15 (m, 6H), 0.85 (t, J=7 Hz, 3H).

Endo-6-(4-butylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[3.2.1]octane(Compound 60B)

Compound 60B was prepared following the procedure as described for thesynthesis of compound 60A (see Scheme 11) using butane-1-thiol andendo-6-(4-iodo-1H-pyrazol-3-yl)-1-azabicyclo[3.2.1]-octane (50).Compound 60B was reacted with 1 equivalent of fumaric acid in EtOH andconcentrated. Yield: 49% (amorphous). LCMS (method A); R_(t): 1.71 min,([M+H]⁺=266). ¹H-NMR (600 MHz, D₆DMSO): δ 7.80 (s, 1H), 6.46 (s, 2H),3.94-3.89 (m, 1H), 3.86-3.81 (m, 1H), 3.79-3.74 (m, 1H), 3.45-3.41 (m,1H), 3.31-3.22 (m, 3H), 2.93-2.89 (m, 1H), 2.62-2.55 (m, 2H), 2.21-2.11(m, 1H), 1.66-1.59 (m, 1H), 1.49-1.42 (m, 2H), 1.40-1.33 (m, 2H),1.26-1.20 (m, 2H), 0.86 (t, J=7 Hz, 3H).

3-(4-Bromo-isoxazol-3-yl)-pyridine (Compound 64, Scheme 12)

To a solution of anhydrous THF (250 ml) containing 3-pyridinealdoxim(61) (18.87 g, 154.7 mmol) were added 20.57 g (1.0 eq) ofN-chlorosuccinimide. After the addition, the resulting solution wasstirred for 18 hours at 65° C. Then the temperature of the reactionmixture was lowered to −30° C. and 1,2-bis-trimethylsilanyl-ethyne wasadded (26.4 g, 170.4 mmol), subsequently followed by triethylamine (2eq, 42 ml, dropwise), while keeping the temperature <−25° C. Afterstirring for another 30 minutes, the mixture was allowed to warm toambient temperature, diluted with ethyl acetate, washed three times witha saturated NaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated.The resulting residue was purified by flash chromatography (diethylether/PE 1/1) to afford3-(4,5-bis-trimethylsilanyl-isoxazol-3-yl)-pyridine (62) as an oil (4.45g, 17%). ¹H-NMR (400 MHz, CDCl₃): δ 8.70 (dd, J=5 Hz, 2 Hz, 1H), 8.68(d, J=2 Hz, 1H), 7.76 (dt, J=8 Hz, 2 Hz, 1H), 7.41-7.37 (m, 1H), 0.46(s, 9H), 0.011 (s, 9H).

To a solution of anhydrous CCl₄ (80 ml) containing compound 62 (4.45 g,15.4 mmol) was added (1.1 eq, 1.04 ml) Br₂. After the addition, theresulting solution was stirred for 18 hours at 40° C. The reactionmixture was cooled and concentrated in vacuo. Ethyl acetate was addedand the organic layer was washed with a saturated NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo. Purification by flashchromatography (diethyl ether) afforded3-(4-bromo-5-trimethylsilanyl-isoxazol-3-yl)-pyridine (63) as an oil(4.5 g, ˜100%). ¹H-NMR (400 MHz, CDCl₃) δ 9.08 (d, J=2 Hz, 1H), 8.73(dd, J=5 Hz, 2 Hz, 1H), 8.14 (dt, J=8 Hz, 2 Hz, 1H), 7.46-7.41 (m, 1H),0.40 (s, 9H).

To a solution of EtOH (20 ml) containing compound 63 (4.5 g, 15.4 mmol)were added 5 ml of 25% NH₄OH. After the addition, the resulting solutionwas stirred for 10 minutes at room temperature. The reaction mixture wasconcentrated in vacuo. Ethyl acetate was added and the organic layer waswashed with a saturated NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification by flash chromatography (diethylether) afforded the title compound (64) as an oil (2.76 g, 82%). (TLCdiethyl ether R_(f) 0.4). ¹H-NMR (400 MHz, CDCl₃): δ 9.14 (d, J=2 Hz,1H), 8.76 (dd, J=5 Hz, 2 Hz, 1H), 8.58 (s, 1H), 8.19 (dt, J=8 Hz, 2 Hz,1H), 7.48-7.43 (m, 1H).

3-(4-Butylsulfanyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 66A, Scheme 12)

To a degassed solution of dioxane (40 ml) containing 64 (1.0 g, 4.44mmol), were added 1.2 eq (0.62 ml) of butane-1-thiol and 2 eq oftriethylamine (1.52 ml). The resulting mixture was stirred for another 2hours under N₂. Successively were added 2.5 mol % of Pd₂(dba)₃ (100 mg)and 5 mol % of Xantphos (128 mg). After the addition, the resultingsolution was stirred for 18 hours at 95° C. under N₂. After cooling toroom temperature, the mixture was diluted with ethyl acetate, washedwith a saturated NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated. The resulting residue was purified by flash chromatography(diethyl ether) to afford 3-(4-butylsulfanyl-isoxazol-3-yl)-pyridine(65A) as an oil (0.26 g, 25%). (TLC diethyl ether R_(f) 0.54). ¹H-NMR(400 MHz, CDCl₃): δ 9.24 (d, J=2 Hz, 1H), 8.72 (dd, J=5 Hz, 2 Hz, 1H),8.49 (s, 1H), 8.31 (dt, J=8 Hz, 2 Hz, 1H), 7.45-7.41 (m, 1H), 2.61 (t,J=7 Hz, 2H), 1.52-1.43 (m, 2H), 1.39-1.29 (m, 2H), 0.83 (t, J=7 Hz, 3H).

1 Eq of sulfuric acid dimethyl ester (0.14 ml, 1.5 mmol) was added to asolution of 65A (0.35 g, 1.5 mmol) in acetone (20 ml) and the mixturewas stirred for 18 hours at room temperature. The precipitated crystalswere filtered, washed extensively with diethyl ether and dried to affordthe corresponding pyridinium sulfuric acid mono methyl ester derivative.To a cooled (−30° C.) suspension of this compound in MeOH (25 ml),sodium borohydride (0.17 g, 4.5 mmol) was added in small portions. Themixture was allowed to warm to ambient temperature and poured into asaturated NH₄Cl solution (0° C.). The solvent was (partly) removed underreduced pressure. Ethyl acetate was added and the organic layer waswashed with a saturated NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting residue was purified by flashchromatography (MeOH) to afford the title compound 66A. (amorphous, 1.09g, 73% (overall)). LCMS (method A): R_(t): 1.58 min, ([M+H]⁺=253).¹H-NMR (600 MHz, CDCl₃): δ 8.23 (s, 1H), 7.06-7.04 (m, 1H), 3.40-3.38(m, 2H), 2.68 (t, J=7 Hz, 2H), 2.59 (t, J=7 Hz, 2H), 2.48-2.42 (m, 5H),1.57-1.51 (m, 2H), 1.44-1.37 (m, 2H), 0.90 (t, J=7 Hz, 3H).

3-(4-Hexylsulfanyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 66B)

To a degassed solution of dioxane (30 ml) containing 64 (0.6 g, 2.66mmol) (see Scheme 12), were added 1.2 eq (0.62 ml) of hexane-1-thiol and2 eq of triethylamine (0.92 ml). The resulting mixture was stirred foranother 2 hours under N₂. Successively were added 2.5 mol % of Pd₂(dba)₃(61 mg) and 5 mol % Xantphos (77 mg). After the addition, the resultingsolution was stirred for 18 hours at 95° C. under N₂. After cooling toroom temperature, the mixture was diluted with ethyl acetate, washedwith a saturated NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated. The resulting residue was purified by flash chromatography(diethyl ether) to afford 3-(4-Hexylsulfanyl-isoxazol-3-yl)-pyridine(65B) as an oil (0.25 g, 37%). ¹H-NMR (400 MHz, CDCl₃): δ 9.24 (d, J=2Hz, 1H), 8.73 (dd, J=5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 8.31 (dt, J=8 Hz, 2Hz, 1H), 7.45-7.41 (m, 1H), 2.61 (t, J=7 Hz, 2H), 1.52-1.43 (m, 2H),1.35-1.13 (m, 6H), 0.85 (t, J=7 Hz, 3H).

1 Eq of sulfuric acid dimethyl ester (0.09 ml, 0.95 mmol) was added to asolution of 65A (0.25 g, 0.95 mmol) in acetone (20 ml) and the mixturewas stirred for 18 hours at room temperature. The precipitated crystalswere filtered, washed extensively with diethyl ether and dried to affordthe corresponding pyridinium sulfuric acid mono methyl ester derivative.To a cooled (−30° C.) suspension of this compound in MeOH (25 ml),sodium borohydride (0.144 g, 4 eq.) was added in small portions. Themixture was allowed to warm to ambient temperature and poured into asaturated NH₄Cl solution (0° C.). The solvent was (partly) removed underreduced pressure. Ethyl acetate was added and the organic layer waswashed with a saturated NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting residue was purified by flashchromatography (MeOH) to afford the title compound 66B. (amorphous, 0.72g, 65% (overall)). LCMS (method A); R_(t): 1.92 min, ([M+H]⁺=281).¹H-NMR (400 MHz, CDCl₃): δ 8.23 (s, 1H), 7.06-7.04 (m, 1H), 3.40-3.38(m, 2H), 2.67 (t, J=7 Hz, 2H), 2.59 (t, J=7 Hz, 2H), 2.48-2.42 (m, 5H),1.59-1.51 (m, 2H), 1.41-1.21 (m, 6H), 0.85 (t, J=7 Hz, 3H).

3-(4-Hex-1-enyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 68A, Scheme 13)

To anhydrous THF (30 ml) containing compound 64 (0.64 g, 2.84 mmol),were added 1.5 eq of (E)-hexene-1-ylboronic acid (0.55 g). The resultingmixture was stirred for 2 hours under N₂. Successively were added 2 eqof K₃PO₄ (1.2 g), 2 mol % of Pd(OAc)₂ (13 mg) and 4 mol % of S-Phos (47mg). After the addition, the resulting solution was warmed at 65° C. for18 hours under N₂. After cooling to room temperature, the mixture wasdiluted with ethyl acetate, washed with a saturated NaHCO₃ solution,dried (Na₂SO₄), filtered and concentrated. The resulting residue waspurified by flash chromatography (diethyl ether/PE 1/1) to afford3-(4-hex-1-enyl-isoxazol-3-yl)-pyridine (compound 67A) as an oil (0.47g, 69%). ¹H-NMR (400 MHz, CDCl₃): δ 8.9 (d, J=2 Hz, 1H), 8.72 (dd, J=5Hz, 2 Hz, 1H), 8.49 (s, 1H), 8.0 (dt, J=8 Hz, 2 Hz, 1H), 7.45-7.41 (m,1H), 6.11-5.99 (m, 2H), 2.22-2.14 (m, 2H), 1.46-1.29 (m, 4H), 0.91 (t,J=7 Hz, 3H).

3-(4-Hex-1-enyl-1H-pyrazol-3-yl)-pyridine (67A) was converted to thetitle compound 68A, using the methodology described for the conversionof 65A to 66A (see Scheme 12). Yield: 95% (amorphous). LCMS (method A):R_(t): 1.68 min, ([M+H]⁺=247). ¹H-NMR (400 MHz, CDCl₃): δ 8.28 (s, 1H),6.36-6.30 (m, 1H), 6.09-5.93 (m, 2H), 3.46-3.41 (m, 2H), 2.70 (t, J=7Hz, 2H), 2.52 (s, 3H), 2.51-2.45 (m, 2H), 2.21-2.14 (m, 2H), 1.47-1.31(m, 4H), 0.92 (t, J=7 Hz, 3H).

3-(4 Oct-1-enyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 68B)

To anhydrous THF (20 ml) containing 64 (0.49 g, 2.17 mmol) (see Scheme13), were added 1.5 eq of (E)-octene-1-ylboronic acid (0.51 g). Theresulting mixture was stirred for 2 hours under N₂. Successively wereadded 2 eq of K₃PO₄ (0.92 g), 2 mol % of Pd(OAc)₂ (10 mg) and 4 mol % ofS-Phos (36 mg). After the addition, the resulting solution was warmed at65° C. for 18 hours under N₂. After cooling to room temperature, themixture was diluted with ethyl acetate, washed with a saturated NaHCO₃solution, dried (Na₂SO₄), filtered and concentrated. The resultingresidue was purified by flash chromatography (diethyl ether/PE 1/1) toafford 3-(4 Oct-1-enyl-isoxazol-3-yl)-pyridine (compound 67B) as an oil(0.19 g, 34%). ¹H-NMR (400 MHz, CDCl₃): δ 8.9 (d, J=2 Hz, 1H), 8.72 (dd,J=5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 7.9 (dt, J=8 Hz, 2 Hz, 1H), 7.45-7.40(m, 1H), 6.11-5.99 (m, 2H), 2.21-2.13 (m, 2H), 1.46-1.38 (m, 2H),1.37-1.21 (m, 6H), 0.91 (t, J=7 Hz, 3H).

3-(4 Oct-1-enyl-1H-pyrazol-3-yl)-pyridine (67B) was converted to thetitle compound 68B, using the methodology described for the conversionof 65A to 66A (see Scheme 12). Yield: 54% (amorphous). LCMS (method A);R_(t): 2.0 min, ([M+H]⁺=275). ¹H-NMR (400 MHz, CDCl₃): δ 8.28 (s, 1H),6.32-6.27 (m, 1H), 6.09-5.93 (m, 2H), 3.37-3.33 (m, 2H), 2.61 (t, J=7Hz, 2H), 2.45 (s, 3H), 2.44-2.39 (m, 2H), 2.20-2.12 (m, 2H), 1.48-1.38(m, 2H), 1.37-1.24 (m, 6H), 0.85 (t, J=7 Hz, 3H).

3-(4-Hept-1-ynyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 70A, Scheme 13)

To anhydrous DMF (20 ml) containing compound 64 (1.08 g, 4.8 mmol), wereadded 1.5 eq of hept-1-ynyl-trimethyl-silane (1.21 g), 3 eq of KOAc(1.41 g) and 1 eq of TBAF (1.0 M in THF). The resulting mixture wasstirred for another 2 hours under N₂. Successively were added 10 mol %of Pd(OAc)₂ (108 mg) and 20 mol % of PPH₃ (251 mg). After the addition,the resulting solution was warmed at 90° C. for 18 hours under N₂. Aftercooling to room temperature, the mixture was diluted with ethyl acetate,washed three times with a saturated NaHCO₃ solution, dried (Na₂SO₄),filtered and concentrated. The resulting residue was purified by flashchromatography (diethyl ether/PE 1/1) to afford3-(4-Hept-1-ynyl-isoxazol-3-yl)-pyridine (69A) as an oil (0.34 g, 30%).¹H-NMR (400 MHz, CDCl₃): δ 9.3 (d, J=2 Hz, 1H), 8.7 (dd, J=5 Hz, 2 Hz,1H), 8.58 (s, 1H), 8.34 (dt, J=8 Hz, 2 Hz, 1H), 7.44-7.39 (m, 1H), 2.42(t, J=7 Hz, 2H), 1.65-1.57 (m, 2H), 1.45-1.29 (m, 4H), 0.91 (t, J=7 Hz,3H).

3-(4-Hept-1-ynyl-1H-pyrazol-3-yl)-pyridine (69A) was converted to thetitle compound 70A, using the methodology described for the conversionof 65A to 66A (see Scheme 12). Yield: 50% (amorphous). LCMS (method A):R_(t): 1.78 min, ([M+H]⁺=259). ¹H-NMR (400 MHz, CDCl₃): δ 8.40 (s, 1H),7.18-7.13 (m, 1H), 3.41-3.36 (m, 2H), 2.59 (t, J=7 Hz, 2H), 2.45 (s,3H), 2.45-2.38 (m, 2H), 1.64-1.55-2.12 (m, 2H), 1.46-1.30 (m, 4H), 0.91(t, J=7 Hz, 3H).

3-[5-Bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine(Compound 73, Scheme 14)

To anhydrous THF (100 ml) containing 3-bromo-pyridine (3.29 g, 20.82mmol), were added 1.2 eq of /PrMgCl (12.49 ml, 2M in THF) and theresulting mixture was stirred for 2 hours under N₂ (10° C.).Subsequently 1.2 eq of (CH₃)₃SnCl were added and the reaction mixturewas stirred for 18 hours at room temperature (under N₂). The reactionmixture was quenched with a saturated NH₄Cl solution, diluted with ethylacetate, washed three times with a saturated NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated. The resulting residue was purifiedby flash chromatography (diethyl ether/PE 1/1) to afford3-trimethylstannanyl-pyridine (71) (3.32 g, 66%). LCMS (method A):R_(t): 2.09 min, ([M+H]⁺=242). ¹H-NMR (400 MHz, CDCl₃): δ 8.62 (bs, 1H),8.52 (dd, J=5 Hz, 2 Hz, 1H), 7.76 (dt, J=8 Hz, 2 Hz, 1H), 7.25-7.21 (m,1H), 0.33 (s, 9H), with Sn satellites at 0.41 and 0.27.

To a solution of 71 (0.82 g, 3.4 mmol) in anhydrous toluene (50 ml) wereadded 0.9 eq (1.10 g) of4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (compound72, LCMS (method A): R_(t): 3.60 min, ([M+H]⁺=357)) and the resultingmixture was stirred for 2 hours under N₂ (room temperature). To thisreaction mixture were added 10 mol % of PdCl₂(PPH₃)₂ (240 mg). After theaddition, the temperature was raised to 100° C. and the resultingsolution was stirred for 18 hours under N₂. The reaction mixture wascooled, diluted with ethyl acetate, washed three times with a saturatedNaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated. Theresulting residue was purified by flash chromatography (diethyl etherfollowed by ethyl acetate) to afford3-[5-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine(73) as an oil (385 mg, 36%). LCMS (method A): R_(t): 3.40 min,([M+H]⁺=355). ¹H-NMR (400 MHz, CDCl₃ and HMBC): δ 8.79 (d, J=2 Hz, 1H),8.66 (dd, J=5 Hz, 2 Hz, 1H), 7.91 (dt, J=8 Hz, 2 Hz, 1H), 7.66 (s, 1H),7.44-7.40 (m, 1H), 5.17 (s, 2H), 3.56-3.50 (m, 2H), 0.94-0.87 (m, 2H),0.0 (s, 9H).

3-(5-Pentylsulfanyl-3H-imidazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 76A, Scheme 14)

To a degassed solution of xylene (100 ml) containing 73 (1.82 g, 5.16mmol), were added 1.25 eq (0.80 ml) of pentane-1-thiol and 1.25 eq ofK₂CO₃ (0.8 g). The resulting mixture was stirred for another 2 hoursunder N₂. Successively were added 10 mol % of Pd₂(dba)₃ (470 mg) and 20mol % mmol Xantphos (600 mg). After the addition, the resulting solutionwas stirred for 18 hours at 130° C. under N₂. After cooling to roomtemperature, the mixture was diluted with ethyl acetate, washed with asaturated NaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated.The resulting residue was purified by flash chromatography (diethylether followed by ethyl acetate) to afford3-[5-pentylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine(74A) as an oil (530 mg, 30%) and starting material (73, 380 mg, 21%),¹H-NMR (400 MHz, CDCl₃): δ 9.38 (d, J=2 Hz, 1H), 8.53 (dd, J=5 Hz, 2 Hz,1H), 8.42 (dt, J=8 Hz, 2 Hz, 1H), 7.82 (s, 1H), 7.35-7.30 (m, 1H), 5.43(s, 2H), 3.59-3.54 (m, 2H), 2.66 (t, J=7 Hz, 2H), 1.47-1.38 (m, 2H),1.28-1.10 (m, 4H), 0.96-0.89 (m, 2H), 0.80 (t, J=7 Hz, 3H), 0.0 (s, 9H).

3-[5-Pentylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine(74A) was converted to3-[5-pentylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine(75A) using the methodology described for the conversion of 21A to 22A(see scheme 3). Yield: 75% (amorphous). ¹H-NMR (400 MHz, CDCl₃): δ 7.68(s, 1H), 6.75-6.71 (m, 1H), 5.37 (s, 2H), 3.54-3.46 (m, 4H), 2.67 (t,J=7 Hz, 2H), 2.57 (t, J=6 Hz, 2H), 2.46 (s, 3H), 2.44-2.38 (m, 2H),1.55-1.46 (m, 2H), 1.37-1.24 (m, 4H), 0.94-0.85 (m, 5H), 0.0 (s, 9H).

To a solution of anhydrous THF (20 ml) containing 75A (0.42 g, 1.06mmol) were added 3.18 ml (3 eq) of TBAF (1.0 M in THF) under N₂. Afterthe addition, the resulting solution was refluxed for 18 hours andsubsequently concentrated in vacuo. Ethyl acetate was added and theorganic layer was washed with a concentrated NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting residue waspurified by flash chromatography (MeOH), followed by a furtherpurification on (25 g) SCX-2 (MeOH followed by 1 N NH₃/MeOH) to affordthe title compound 76A. (oil, 0.2 g, 73%). LCMS (Method A): R_(t): 1.0min, ([M+H]⁺=266). ¹H-NMR (400 MHz, CDCl₃): δ 7.54 (s, 1H), 6.36-6.31(m, 1H), 3.49-3.46 (m, 2H), 2.75 (t, J=7 Hz, 2H), 2.64 (t, J=6 Hz, 2H),2.47 (s, 3H), 2.43-2.38 (m, 2H), 1.55-1.49 (m, 2H), 1.35-1.23 (m, 4H),0.85 (t, J=7 Hz, 3H).

3-(5-Hexylsulfanyl-3H-imidazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(Compound 76B, Scheme 14)

To a degassed solution of xylene (30 ml) containing compound 73 (0.6 g,1.70 mmol), were added 1.25 eq (0.30 ml) of hexane-1-thiol and 1.25 eqof K₂CO₃ (0.29 g). The resulting mixture was stirred for another 2 hoursunder N₂. Successively were added 10 mol % of Pd₂(dba)₃ (160 mg) and 20mol % of Xantphos (200 mg). After the addition, the resulting solutionwas stirred for 18 hours at 130° C. under N₂. After cooling to roomtemperature, the mixture was diluted with ethyl acetate, washed with asaturated NaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated.The resulting residue was purified by flash chromatography (diethylether) to afford3-[5-hexylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine(74B) as an oil (120 mg, 18%) and starting material (73, 380 mg), ¹H-NMR(400 MHz, CDCl₃): δ 9.38 (d, J=2 Hz, 1H), 8.53 (dd, J=5 Hz, 2 Hz, 1H),8.42 (dt, J=8 Hz, 2 Hz, 1H), 7.82 (s, 1H), 7.35-7.30 (m, 1H), 5.43 (s,2H), 3.59-3.54 (m, 2H), 2.66 (t, J=7 Hz, 2H), 1.46-1.37 (m, 2H),1.28-1.06 (m, 8H), 0.96-0.89 (m, 2H), 0.80 (t, J=7 Hz, 3H), 0.0 (s, 9H).

To a solution of anhydrous THF (30 ml) containing 74B (0.29 g, 0.74mmol) were added 2.2 ml (3 eq) of TBAF (1.0 M in THF) under N₂. Afterthe addition, the resulting solution was refluxed for 18 hours andsubsequently concentrated in vacuo. Ethyl acetate was added and theorganic layer was washed with a concentrated NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting residue waspurified by flash chromatography (ethyl acetate) to afford3-(5-hexylsulfanyl-3H-imidazol-4-yl)-pyridine. (77) as an oil (0.14 g,71%). ¹H-NMR (400 MHz, CDCl₃): δ 9.25 (bs, 1H), 8.53 (dd, J=5 Hz, 2 Hz,1H), 8.42-8.35 (m, 1H), 7.78 (s, 1H), 7.38-7.34 (m, 1H), 2.79-2.69 (m,2H), 1.53-1.44 (m, 2H), 1.33-1.09 (m, 6H), 0.80 (t, J=7 Hz, 3H).

3-(5-Hexylsulfanyl-3H-imidazol-4-yl]-pyridine (77) was converted to thetitle compound (76B) using the methodology described for the conversionof 21A to 22A (see Scheme 3) (the quaternization however was done atroom temperature with a slight excess of CH₃I). Yield: 70% (oil). LCMS(method A); R_(t): 1.21 min, ([M+H]⁺=280). ¹H-NMR (400 MHz, CDCl₃): δ7.53 (s, 1H), 6.40-6.29 (m, 1H), 3.45-3.41 (m, 2H), 2.79-2.72 (m, 2H),2.59 (t, J=6 Hz, 2H), 2.45 (s, 3H), 2.41-2.37 (m, 2H), 1.55-1.49 (m,2H), 1.38-1.31 (m, 2H), 1.30-1.19 (m, 4H), 0.85 (t, J=7 Hz, 3H).

§5. Pharmacological Tests (I) Assay Method for Muscarinic ReceptorLigand Screening (In Vitro; Functional Assay)

Test Substance

Compounds were dissolved in DMSO (10 mM) and diluted in assay buffer totest concentration. Prime testing was at 1 μM; for actives in antagonistmode (PI, percent inhibition with respect to reference agonist andblank >30%) as well as actives in agonist mode (PS, percent stimulationwith respect to reference agonist and blank >30%) testing was continuedat lower concentrations in 10-fold dilutions: 0.1 μM, 0.01 μM, etc.

Assay Characteristics Target, Species, Tissue

Assay Target Species Tissue Muscarine M1 GPCR-A-MA-ACH M1 Human CHOcells Muscarine M1 GPCR-A-MA-ACH M1 Rabbit vas deferens (field-stimulated) Muscarine M2 GPCR-A-MA-ACH M2 Guinea Pig left atrium(electrically paced) Muscarine M3 GPCR-A-MA-ACH M3 Guinea Pig ileumMuscarine M4 GPCR-A-MA-ACH M4 Human CHO cells

Assay Characteristics Ligand (Kd, Concentration), Non Specific Binding(Compound, Concentration)

Ligand Ligand Reference EC50 Concentration L Reference Assay Agonist(nM) (nM) Antagonist Response Muscarine M1 acetylcholine 0.8  100 (agomode) pirenzepine Ca2+ - FLIPR   3 (anta mode) Fluorimetry Muscarine M1McN-A-343 250  3000 (ago mode) pirenzepine inhibition of  1000 (antamode) twitch contraction Muscarine M2 carbachol 150  3000 (ago mode)methoctramine negative  1000 (anta mode) inotropic effect Muscarine M3carbachol 125  3000 (ago mode) 4-DAMP contraction  1000 (anta mode)Muscarine M4 oxotremorine 40 10000 (ago mode) pirenzepine Ca2+ -Aequorin 10000 (anta mode) luminescence

Assay Characteristics Method, Bibliography

Assay Method (see below) Bibliography (see below) Muscarine M1cell-based assay Sur et al. (2003) Muscarine M1 isolated organ Eltze(1988) Muscarine M2 isolated organ Eglen at al. (1988) Muscarine M3isolated organ Clague et al. (1985) Muscarine M4 cell-based assayStables et al. (1997)

Assay Procedures & Calculations

Assay Procedures

Isolated Organ Assays, Agonist Mode:

The tissues were exposed to a maximal concentration of the respectivereference agonist to verify responsiveness and to obtain a controlresponse. Following extensive washings and recovery of the initialstate, the tissues were exposed to the test compounds or the sameagonist. In the M1 and M2 receptor assays, the compounds were left incontact with the tissues until a stable response was obtained or for amaximum of 15 min. When several concentrations were tested, they wereadded cumulatively. In the M3 receptor assay, the compounds were left incontact with the tissues for a time sufficient to obtain a peak responseor for a maximum of 10 min, then washed out. When several concentrationswere tested, they were added consecutively at 40-min intervals. Where anagonist-like response was obtained, the respective reference antagonistwas tested against the highest concentration of the compounds to confirmthe involvement of the receptor studied in this response.

Isolated Organ Assays, Antagonist Mode:

The tissues were exposed to a submaximal concentration of the respectivereference agonist to obtain a control response. In the M1 and M2receptor assays, the test compounds or the reference antagonists wereadded after stabilization of the agonist-induced response then left incontact with the tissues until a stable effect was obtained or for amaximum of 15 min. When several concentrations were tested, they wereadded cumulatively. In the M3 receptor assay, the test compounds or thereference antagonist were added 30 min before re-exposure to the agonistwhich was added at 40-min intervals. Where it occurred, an inhibition ofthe agonist-induced response produced by the compounds indicated anantagonist activity at the receptor studied. Each compound wasinvestigated in the three assays for agonist and antagonist activitiesat one or several concentrations in three separate tissues. In eachassay, the reference agonist and antagonist were tested at severalconcentrations in three separate tissues to obtainconcentration-response curves.

Cell-Based Assays:

Cells were incubated with compound and the response indicated wasmeasured.

Response and Calculation of Results

Isolated Organ Assays:

The parameters measured were the maximum change in the amplitude of theelectrically-evoked contractions (M1 and M2 receptor assays) or intension (M3 receptor assay) induced by each compound concentration. Theresults are expressed as a percent of the control agonist-inducedresponse. The EC50 values of the reference agonists (concentrationproducing a half-maximum response) and IC50 values of the referenceantagonists (concentration producing a half-maximum inhibition of theagonist-induced response) were calculated by linear regression analysisof their concentration-response curves.

Cell-Based Assays:

The results are expressed as a percent of reference agonist values andblanks in the presence of the test compound, percent stimulation foragonist mode; for the antagonist mode (test compound in the presence ofreference agonist) as percent inhibition. The EC50 values (concentrationcausing a half-maximal stimulation of control values), IC50 values(concentration causing a half-maximal inhibition of control values) weredetermined by non-linear regression analysis of theconcentration-response curves using Hill equation curve fitting.

Bibliography

-   CLAGUE, R. U., EGLEN, R. M., STRACHAN, A. C. and    WHITING, R. L. (1985) Action of agonists and antagonists at    muscarinic receptors present on ileum and atria in vitro. Brit. J.    Pharmacol, 86: 163-170.-   EGLEN, R. M., MONTGOMERY, W. W., DAINTY, I. A., DUBUQUE, L. K. and    WHITING, R. L. (1988) The interaction of methoctramine and himbacine    at atrial, smooth muscle and endothelial muscarinic receptors in    vitro. Brit. J. Pharmacol., 95: 1031-1038.-   ELTZE, M. (1988) Muscarinic M1- and M2-receptors mediating opposite    effects on neuro-muscular transmission in rabbit vas deferens.    Eur. J. Pharmacol., 151: 205-221.-   STABLES, J., GREEN, A., MARSHALL, F., FRASER, N., KNIGHT, E.,    SAUTEL, M., MILLIGAN, G., LEE, M., and REES, S. (1997) A    bioluminescent assay for agonist activity at potentially any    G-Protein-Coupled Receptor. Anal. Biochem. 252: 115-126.-   SUR, C., MALLORGA, P. J., WITTMANN, M., JACOBSON, M. A., PASCARELLA,    D., WILLIAMS, J. B., BRANDISH, P. E., PETTIBONE, D. J.,    SCOLNICK, E. M. and CONN, P. J. (2003) N-desmethylclozapine, an    allosteric agonist at muscarinic 1 receptor, potentiates    N-methyl-D-aspartate receptor activity. PNAS, 100: 13674-13679.

(II) Assay Method for Muscarinic Receptor Ligand Screening (In Vitro;Receptor Binding Assay)

Test Substance

Compounds were dissolved in DMSO (10 mM) and diluted in assay buffer totest concentration. Prime testing was at 10 μM; for actives (PI, percentinhibition with respect to total and non-specific binding >40%) testingwas continued at lower concentrations in 10-fold dilutions: 1 μM, 0.1μM, etc.

Assay Characteristics Target. Species, Tissue

Assay Target Species Tissue Muscarine M non- GPCR-A-MA-ACH M Ratcerebral cortex selective Muscarine M1 GPCR-A-MA-ACH M1 Human CHO cellsMuscarine M2 GPCR-A-MA-ACH M2 Human CHO cells Muscarine M3 GPCR-A-MA-ACHM3 Human CHO cells Muscarine M4 GPCR-A-MA-ACH M4 Human CHO cells

Assay Characteristics Ligand (Kd, Concentration), Non Specific Binding(Compound, Concentration)

Non Specific Ligand Non Specific Binding Ligand Concentration BindingConcentration Assay Ligand Kd (nM) L (nM) Compound (μM) Muscarine M non-3H-QNB 0.01 0.05 Atropine 1 μM selective Muscarine M1 3H-Pirenzepine 132 Atropine 1 μM Muscarine M2 3H-AFDX384 4.3 2 Atropine 1 μM Muscarine M33H-4DAMP 0.5 0.2 Atropine 1 μM Muscarine M4 3H-Oxotremorine 4.5 6Atropine 1 μM Muscarine M4 3H-4DAMP 0.332 0.2 Atropine 1 μM

Assay Characteristics Incubation Conditions (period/temperature),Bibliography

Incubation Conditions Assay period/temperature Bibliography (see below)Muscarine M non- 120 min/22° C.  Richards (1990) selective Muscarine M160 min/22° C. Dörje et al. (1991) Muscarine M2 60 min/22° C. Dörje etal. (1991) Muscarine M3 60 min/22° C. Peralta et al. (1987) Muscarine M430 min/25° C. Dörje et al. (1991) Muscarine M4 60 min/22° C. Dörje etal. (1991)

Assay Procedures & Calculations

Assay Procedure

Following incubation of compound with the receptor preparation (from‘Tissue’) and the Ligand at the time and temperature indicated, thereceptor preparations were rapidly filtered under vacuum through glassfibre filters; the filters were washed extensively with an ice-coldbuffer using a harvester. Bound radioactivity was measured byscintillation counting using a liquid scintillation cocktail.

Response and Calculation of Results

Results were expressed as percentage of total Ligand binding and that ofNon Specific Binding, per concentration of Compound tested (duplicates);from the concentration—displacement curves IC50 values were determinedby non-linear regression analysis using Hill equation curve fitting. Theinhibition constants (Ki) were calculated from the Cheng-Prushoffequation Ki=IC50/(1+L/Kd), where L is the concentration of radioligandin the assay, and Kd the affinity of the radioligand for the receptor.Results were expressed as pki's, means±SD of at least 2 separateexperiments; i.e. outliers (outside +/−1 std of mean) and discrepancieswere excluded. Compounds with no significant affinity at concentrationsof 10 μM and higher were concluded to be “inactive” denoted by pKi of“<5.0”.

Bibliography

-   DÖRJE, F., WESS, J., LAMBRECHT, G., TACKE, R., MUTSCHLER, E. and    BRANN, M. R. (1991) Antagonist binding profiles of five cloned human    muscarinic receptor subtypes. J. Pharmacol. Exp. Ther., 256:    727-733.-   RICHARDS, M. H. (1990) Rat hippocampal muscarinic autoreceptors are    similar to the M₂ (cardiac) subtype: comparison with hippocampal M₁,    atrial M₂ and ileal M3 receptors. Brit. J. Pharmacol., 99: 753-761.-   PERALTA, E. G., ASHKENAZI, A., WINSLOW, J. W., SMITH, D. H.,    RAMACHANDRAN, J. and CAPON, D. J. (1987) Distinct primary    structures, ligand-binding properties and tissue-specific expression    of four human muscarinic acetylcholine receptors. EMBO. J., 6:    3923-3929.

Determination of Metabolic Stability (In Vitro)

Method used according to procedures described by DI, L. et al., Journalof Biomolecular Screening, Vol. 8, No. 4, 453-462 (2003).

§6. Pharmacological Data

TABLE 1 Affinity to M1 and M4 receptors and efficacy. RB RB RB Musc.Musc. M4 Cell funct. Musc. M1 Cell funct. Com- M4 3H- 3H- Musc. M4 3H-Musc. M1 pound DAMP Oxotremorine Agonism Pirenzepine Agonism No pKi pKipEC50 pKi pEC50  9 6.5 6.4 <5.0 5.9 6.9 16 n.d. n.d. <5.0 n.d. n.d. 22F7.4 7.2 6.9 6.5 6.7 22M 6.4 6.6 <5.0 6.3 n.d. 26 6.7 6.6 <5.0 6.8 n.d.49A 7.8 7.6 7.4 6.9 8.0 22N 6.6 6.6 <5.0 6.4 n.d. 22B 6.9 6.4 6.3 6.37.1 41 <5 <5 <5.0 <5 n.d. 22A 6.4 6.6 <5.0 5.8 n.d. 22E 6.5 7 <5.0 6.4n.d. 42 5.3 5.4 <5.0 5.1 n.d. 22G 7.3 6.7 6.5 6.7 7.4 22D 6.4 6.5 <5.05.8 n.d. 33C 6.5 5.8 5.9 5.9 6.9 22Q 6.3 6.9 <5.0 6.1 n.d. 22R 5.4 5.7<5.0 4.9 n.d. 22S 7.3 6.8 <5.0 6.9 6.4 33A 6.6 6.3 6.1 5.9 6.9 22H 7.26.9 8.0 6.7 6.9 33D 6.0 5.8 5.9 5.6 7.0 66B 7.0 6.8 6.3 6.2 n.d. 66A 7.47.1 <5.0 6.6 n.d. 68B 6.0 6.1 6.1 5.3 6.1 70A 6.7 6.6 6.2 6.0 6.6 47A6.1 6.6 6.3 5.6 6.8 68A 6.6 6.2 6.1 5.8 6.7 45B 5.9 6.3 6.5 5.7 6.9 49D7.0 6.9 6.8 6.1 7.4 60B 6.8 6.6 <5.0 6.4 <6.0 49E 7.4 7.1 7.1 6.5 8.045C 6.1 6.3 5.7 6.1 <6.0 45A 6.2 6.4 6.1 5.8 6.9 47B 6.5 6.8 <5.0 6.1n.d. 45E 5.8 5.8 <5.0 5.8 <6.0 22C 7.2 6.8 <5.0 6.6 <6.0 45D 6.2 6.3 5.95.7 6.1 47C 6.1 6.6 6.2 6.1 6.1 22I 6.6 7.0 6.6 6.1 7.0 22J 6.6 7.2 6.66.2 7.4 22K 6.2 6.4 5.9 5.9 7.0 49F 7.3 7.9 7.9 6.6 6.1 49B 7.6 8.1 8.26.8 8.0 49H 7.4 7.5 <5.0 6.8 7.3 33B 6.5 6.7 6.3 6.0 7.0 33G 6.7 6.9 6.25.8 7.6 49C 6.9 6.9 6.3 6.0 7.1 22L 7.0 7.2 7.2 6.1 8.0 22O 6.1 6.4 6.25.1 7.5 33E 6.5 6.8 6.2 6.0 6.7 33F 6.3 6.5 6.1 5.4 7.4 59 7.0 6.7 <5.06.0 7.1 49G 7.0 7.6 8.0 6.2 7.3 52C 6.6 7.2 n.d. 6.0 7.9 52A 6.6 6.9n.d. 6.1 7.7 52B 6.9 7.2 7.0 6.2 8.1 49I 7.2 7.9 7.7 6.5 8.5 22P 5.2 5.25.9 <5.0 6.4 76B 6.3 6.0 6.0 5.4 7.1 76A 6.5 6.2 5.1 5.6 6.9 60A 6.6 7.2<5.0 6.4 n.d. (RB = receptor binding; n.d. = not done)

TABLE 2 Affinity to M2 and M3 receptors and efficacy. Cell Cell Cellfunct. funct. Cell funct. funct. RB Musc Musc. M2 Musc. M2 RB Musc Musc.M3 Musc. M3 Compound M2 Agonism Antagonism M3 Agonism Antagonism Nomethoctramine pEC50 pA2 4-DAMP pEC50 pA2 22J 5.5 <6 <6 6.5 <6 <6 33G 5.4<6 <6 6.1 <6 <6 33B 5.9 <6 <6 6.4 <6 <6 22L 5.7 <6 <6 6.5 <6 <6 33F 5.3<6 <6 6.0 <6 <6 22O 5.0 <6 7.7 5.6 <6 <6 49G 6.1 <6 <6 6.5 <6 <6 52A 5.4<6 <6 6.1 <6 <6 52C 5.6 <6 <6 6.2 <6 <6 52B 5.9 <6 7.6 6.5 <6 <6 76B 5.2<6 <6 5.6 <6 <6 76A 5.3 <6 <6 6.1 <6 <6 49E 6.3 6.1 <6 6.9 <6 <6 22S 5.7<6 <6 7.3 <6 7.0 22C 6.4 <6 <6 7.5 <6 <6 49F 6.4 <6 <6 7.0 <6 <6 49B 6.2<6 <6 7.2 <6 <6 Methoctramine 7.5 7.9 4-DAMP 9.4 Carbachol 6.8 McN-A-3436.9 Pirenzepine 8.9 (RB = receptor binding)

TABLE 3 Stability in human liver homogenate/selected compounds Compoundt ½ (minutes) 22B 52 22G 50 22J 129 22L 56 22O 245 33F 230 33G 56Xanomeline 17 (reference)

1. A heterocyclic compound of the formula (I)

or a pharmaceutically acceptable salt, a solvate or hydrate thereof,wherein the heterocycle comprises two double bonds, which may be presentat varying positions, and which are represented by the dashed lines(---); the heterocycle contains two heteroatoms, W is N or NH; Y is CH,O or NH, wherein if Y is O, X₁ is CH and X₂ is C-Z-R2 or C—R3, wherein Zis NH, O, or S; and if Y is CH or NH, one of X₁ and X₂ is CH or N,wherein if X₁ is CH or N, X₂ is C-Z-R2 or C—R3, and if X₂ is CH or N, X₁is C-Z-R2 or C—R3, wherein Z is NH or S; R1 is chosen from structures(a), (b) and (c):

R2 is chosen from (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl and (C₂-C₁₀)alkynyl,optionally independently substituted with one or more substituentschosen from halogen, hydroxy, cyano, oxo, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, (C₁-C₆)alkenyloxy, (C₁-C₆)alkenylthio,(C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₅-C₇)cycloalkyl, a 5-membered unsaturatedheterocycle optionally substituted with halogen, phenyl, phenyloxy andphenylthio, wherein the phenyl group is optionally substituted withhalogen; and R3 is chosen from (C₄-C₁₀)alkyl, (C₂-C₁₀)alkenyl and(C₂-C₁₀)alkynyl, optionally independently substituted with one or moresubstituents chosen from halogen, hydroxy, cyano, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, (C₁-C₆)alkenyloxy, (C₁-C₆)alkenylthio,(C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₅-C₇)cycloalkyl, a 5-membered unsaturatedheterocycle optionally substituted with halogen, phenyl, phenyloxy andphenylthio, wherein the phenyl group is optionally substituted withhalogen; and optionally, when R2 is an unbranched (C₂-C₈)alkyl, R2 linksto formula (Ia)

or a pharmaceutically acceptable salt, a solvate or hydrate thereof,through the X₁a or X₂a of formula (Ia), wherein if X₁ is CH or N, X₁a isCH or N and X₂a is C-Za-, or if X₁ is C-Z-R2, X₁a is C-Za- and X₂a is CHor N, wherein X₁a or X₂a having Za links to R2; wherein Wa is N or NH;Ya is CH, O or NH; Za is NH, O, or S; and R₁a is chosen from structures(a) (b) and (c):


2. The compound of claim 1, wherein R2 is chosen from (C₁-C₁₀)alkyl,(C₂-C₁₀)alkenyl and (C₂-C₁₀)alkynyl, optionally independentlysubstituted with one or more substituents chosen from halogen, hydroxy,cyano, oxo, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkenyloxy,(C₁-C₆)alkenylthio, (C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₅-C₇)cycloalkyl, a5-membered unsaturated heterocycle optionally substituted with halogen,phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionallysubstituted with halogen.
 3. The compound of claim 2, wherein R2 ischosen from (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl, optionallyindependently substituted with one or more substituents chosen fromhalogen, hydroxy, cyano, (C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkoxy,(C₅-C₇)cycloalkyl, tetrahydrofuranyl and phenyl, wherein the phenylgroup is optionally substituted with halogen.
 4. The compound of claim3, wherein R2 is chosen from (C₁-C₈)alkyl and (C₂-C₈)alkenyl, optionallysubstituted with one or more substituents chosen from halogen and(C₁-C₆)alkoxy.
 5. The compound of claim 1, wherein R3 is chosen from(C₄-C₁₀)alkyl, (C₂-C₁₀)alkenyl and (C₂-C₁₀)alkynyl, optionallysubstituted with a substituent chosen from (C₅-C₇)cycloalkyl and phenyl,wherein the phenyl group is optionally substituted with halogen.
 6. Thecompound of claim 1, wherein R1 has the structure (a).
 7. The compoundof claim 1, wherein W is N and Y is NH.
 8. The compound of claim 7,wherein X₁ is CH and X₂ is C-Z-R2 or C—R3, and Z is O or S.
 9. Thecompound of claim 8, wherein X₂ is C-Z-R2.
 10. The compound of claim 9,wherein Z is S.
 11. The compound of claim 1, wherein Y is O and Z is Oor S.
 12. The compound of claim 11, wherein Z is S.
 13. The compound ofclaim 1, wherein the compound is chosen from3-(4-Pentyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Butyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Butylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-[4-(Furan-2-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;3-(5-Butylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Butylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane;3-(4-Benzylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-[4-(4,4,4-trifluoro-butylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;N-[3-(1-Methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-yl]-butyramide;3-(4-Methylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Propylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;Butyl-[3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-yl]-amine;3-(4-Pentylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Ethylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Butyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Allylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-[3-(1-Methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-ylsulfanyl]-propionitrile;3-[4-(3-Methyl-butylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;3-[4-(3-Phenyl-propoxy)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Hexylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-But-3-enyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Hexylsulfanyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Butylsulfanyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4 Oct-1-enyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Hept-1-ynyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Hex-1-enyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Hex-1-enyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Hept-1-ynyl-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Ethylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane;Endo-6-(4-butylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[3.2.1]octane;3-(4-Propylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane;3-(4-Non-1-ynyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Hex-1-ynyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-{4-[2-(3-Fluoro-phenyl)-vinyl]-1H-pyrazol-3-yl}-1,2,5,6-tetrahydro-1-methylpyridine;3-[4-(5-Cyclohexyl-pent-1-ynyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;Bis-[3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-yl]-2-sulfanylethyl]-methane;3-[4-(5-Phenyl-pent-1-ynyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;3-(4 Oct-1-enyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-[4-(3-Phenyl-propylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;3-[4-(4,4-Difluoro-but-3-enylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;3-[4-(3-Phenyl-allylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Hexylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane;3-(4-Pentylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane;3-[4-(3-Methyl-butylsulfanyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane;3-(4-Hexyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Pentyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Methylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane;3-[4-Pent-4-enylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;3-[4-(2-Ethoxy-ethylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Heptyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Heptyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-Pent-4-enyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;Endo-6-(4-iodo-1H-pyrazol-3-yl)-1-azabicyclo[3.2.1]octane;3-(4-Phenethylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane;3-(4-Pentyloxy-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane;3-(4-Butoxy-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane;3-(4-Propoxy-1H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane;3-[4-(4,4-Difluoro-but-3-enylsulfanyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane;3-[4-[2-(2-Methoxy-ethoxy)-ethylsulfanyl]-1H-pyrazol-3-yl}-1,2,5,6-tetrahydro-1-methylpyridine;3-(5-Hexylsulfanyl-3H-imidazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(5-Pentylsulfanyl-3H-imidazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine,and Endo-6-(4-pentylsulfanyl-1H-pyrazol-3-yl)-1-azabicyclo[3.2.1]octane;or a pharmaceutically acceptable salt, a solvate or hydrate thereof. 14.A pharmaceutical composition comprising a compound as claimed in claim1, and at least one other pharmacologically active substance.
 15. Apharmaceutical composition comprising the compound as claimed in claim1, and a pharmaceutically acceptable auxiliary.
 16. A method oftreating, alleviating or preventing muscarinic receptor mediateddiseases and conditions comprising administering a compound as claimedin claim 1, to a patient in need thereof.
 17. The method of claim 16,wherein the muscarinic receptor is one or more of M1 and M4.
 18. Themethod of claim 16, wherein the diseases and conditions are chosen fromcognitive impairment and psychotic disorders.
 19. A method for treatingalleviating or preventing muscarinic receptor mediated diseases andconditions comprising administering a compound as claimed in claim 1,and at least one other pharmacologically active substance, to a patientin need thereof.
 20. A heterocyclic compound of the formula (II)

or a pharmaceutically acceptable salt, a solvate or hydrate thereof,wherein the heterocycle comprises two double bonds, which may be presentat varying positions, and which are represented by the dashed lines(---); the heterocycle comprises two heteroatoms, W* is N, NH orN-2-(trimethylsilyl)ethoxymethyl; Y* is CH, O, N or NR4, wherein R4 ischosen from H, 2-(trimethylsilyl)-ethoxymethyl, —SO₂N(CH₃)₂ and—SO₂phenyl; wherein if Y* is O, X₁* is CH and X₂* is C-Z*-R2* or C—R3*,wherein Z* is NH, O, or S; and if Y* is CH or NH, one of X₁* and X₂* isCH or N, wherein if X₁* is CH or N, X₂* is C-Z*-R2* or C—R3*, and if X₂*is CH or N, X₁* is C-Z*-R2* or C—R3*, wherein Z* is NH or S; R2* ischosen from (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl, optionallyindependently substituted with one or more substituents chosen fromhalogen, hydroxy, cyano, oxo, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,(C₁-C₆)alkenyloxy, (C₁-C₆)alkenylthio, (C₁-C₄)alkoxy(C₁-C₄)alkoxy,(C₅-C₇)cycloalkyl, a 5-membered unsaturated heterocycle optionallysubstituted with halogen, phenyl, phenyloxy, and phenylthio, wherein thephenyl group is optionally substituted with halogen; and R3* is chosenfrom (C₄-C₁₀)alkyl, (C₂-C₁₀)alkenyl and (C₂-C₁₀)alkynyl, optionallyindependently substituted with one or more substituents chosen fromhalogen, hydroxy, cyano, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,(C₁-C₆)alkenyloxy, (C₁-C₆)alkenylthio, (C₁-C₄)alkoxy(C₁-C₄)alkoxy,(C₅-C₇)cycloalkyl, a 5-membered unsaturated heterocycle optionallysubstituted with halogen, phenyl, phenyloxy and phenylthio, wherein thephenyl group is optionally substituted with halogen; and optionally,when R2* is an unbranched (C₂-C₈)alkyl, R2* links to formula (IIa)

or a pharmaceutically acceptable salt, a solvate or hydrate thereof,through X₁*a or X₂*a of formula (IIa), wherein if X₁* is CH or N, X₁*ais CH or N and X₂*a is C-Z*a-, or if X₁* is C-Z*-R2*, X₁*a is C-Z*a- andX₂*a is CH or N, wherein X₁*a or X₂*a having Z*a links to R2*; whereinW*a is N, NH or N-2-(trimethylsilyl)ethoxymethyl; Y*a is CH, O, N orNR4, wherein R4 is chosen from H, 2-(trimethylsilyl)-ethoxymethyl,—SO₂N(CH₃)₂ and —SO₂-phenyl; and Z*a is NH, O, or S.
 21. A heterocycliccompound of the formula (III)

wherein R5 is H and R6 is Br, or R5 is —Si(CH₃)₃ and R6 is Br or—Si(CH₃)₃.